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DISEASE 
OF   THE    PANCREAS 

ITS  CAUSE  AND  NATURE 

By 

EUGENE  L.  OPIE 

PROFESSOR   OF    PATHOLOGY,  WASHINGTON    UNIVERSITY,  ST.  LOUIS,  MO. 

FORMERLY  MEMBER  OF  THE  ROCKEFELLER  INSTITUTE  FOR  MEDICAL   RESEARCH 

AND    PATHOLOGIST   TO   THE   PRESBYTERIAN    HOSPITAL 

OF   NEW   YORK    CITY 

SECOND  EDITION  REWRITTEN 

ILLUSTRATED 


PHILADELPHIA    &    LONDON 
J.    B.    LIPPINCOTT    COMPANY 

1910 


COPYBIGHT   1903,   BT  J.   B.   LiPPINCOTT  COMPANY 


COPYKIOHT    1910,   BY   J.    B.   LiPPINCOTT   COMPANY 


Printed  by  J.  B.  Lippincott  Company 
The  Washington  Square  Press,  Philadelphia,  U.S.A. 


Dedicated 

WITH 

Gratitude  and  Affection 

TO 

WILLIAM  H.  WELCH 


Digitized  by  the  Internet  Archive 

in  2010  with  funding  from 

Open  Knowledge  Commons 


http://www.archive.org/details/diseaseofpancreaOOopie 


PREFACE 


HISTORY 


The  monograph  of  Friedreich/  which  contains  the 
meagre  clinical  data  published  before  1875,  is  the  first 
systematic  description  of  pancreatic  disease.  Available 
to  Friedreich  were  the  rnonograyjhs  of  Claessen  ^  (1842) 
and  of  Ancelet  ^  (1866),  together  with  a  considerable 
mass  of  carefully  described  cases  and  pathological  rec- 
ords collected  by  Cruveilhier,  Rokitansky,  Virchow, 
Klebs,  and  others.  The  part  of  pancreatic  secretion  in 
the  digestion  of  proteins,  fats,  and  carbohydrates  had 
been  recognized  by  Claude  Bernard."*  Nevertheless, 
symptoms  produced  by  lesions  of  the  gland  were  so 
ill-defined  that  diagnosis  of  pancreatic  disease  was  im- 
possible; advance  of  clinical  knowledge  has  been  depen- 
dent upon  a  clearer  understanding  of  the  peculiar 
pathology  of  the  organ. 

Studies  of  Heidenhain  ^  have  shown  what  changes 
occur  in  the  gland  during  the  elaboration  of  the  pan- 
creatic enzymes,  and  have  prepared  the  way  for  an 
understanding  of  the  process  of  secretion  in  general. 

^  Friedreich :  Disease  of  the  Pancreas.  Von  Ziemssen's  Practice  of 
Medicine  [Trans.],  New  York,  1878,  viii,  551. 

"  Claessen :  Krankheiten  der  Bauchspeieheldriise,  Koln,  1842. 

^  Ancelet :    Etude  sur  les  maladies  du  pancreas,  Paris,  1866. 

^  Claude  Bernard :  Memoire  sur  le  pancreas.  Compt.  rend,  de 
I'Aead.  de  scien.,  1856,  Suppl.,  379. 

''  Heidenhain :  Beitrage  zur  Kenntniss  des  Pankreas.  Pflugar's 
Arch.,  1875,  x,  557. 

V 


vi  PREFACE 

Langerhans^  (1869)  has  shown  that  the  pancreas  con- 
tains, in  addition  to  the  secreting  cells,  morphological 
elements  which  find  little  analogy  in  other  glands; 
throughout  the  parenchyma  are  isolated  bodies  composed 
of  cells  having  no  relation  to  the  ducts  of  the  gland, 
but  in  intimate  contact  with  a  rich  vascular  supply.  Re- 
cent progress  of  the  physiology  of  the  pancreas  is 
marked  by  the  discovery  of  enterokinase  by  Schepowal- 
nikow,  a  pupil  of  Pawlow,^  and  of  secretin  by  Bayliss  and 
Starling.**  In  Chapters  IV  and  V  the  physiology  of  the 
gland  will  be  briefly  reviewed. 

Friedreich  described  acute  primary  pancreatitis, 
acute  secondary  pancreatitis  (parenchymatous  degeiiera- 
tion),  and  chronic  pancreatitis,  and  recognized,  follow- 
ing Klebs,  the  hemorrhagic  character  not  infrequently 
exhibited  by  the  acute  lesions.  A  classification  of  acute 
pancreatic  disease,  proposed  by  Fitz  ^  in  1889,  has  been 
almost  universally  accepted;  he  has  distinguished  three 
types  of  inflammation,  characterized  as  hemorrhagic, 
gangrenous,  and  suppurative  pancreatitis,  and  has  care- 
fully described  the  symptoms  which  accompany  these 
lesions.  So-called  gangrenous  inflammation  of  the  pan- 
creas represents  in  most  instances,  at  least,  a  late  stage 
of  the  hemorrhagic  lesion,  and  both  are  peculiar  to  the 

"  Langerhans:  Beiti'iige  zur  niikioskopischen  Anatomie  der  Bauch- 
speicheldriise.     Inaug.  Diss.,  1869. 

^Pawlow:  The  Work  of  the  Digestive  Glands  [Trans.],  Lon- 
don, 1902. 

"  Bayliss  and  Starling :  The  Mechanism  of  Pancreatic  Secretion. 
Jour,  of  Physiol.,  1902,  xxviii,  325;  Starling,  Physiology  of  Digestion, 
Chicago,  1906. 

"Fitz:  Acute  Pancreatitis.  Med.  Record,  1889,  xxxv,  197,  225, 
253. 


PREFACE  vii 

pancreas,  for  the.y  have  characters  not  produced  by 
changes  in  other  organs.  Recent  observations  and  ex- 
periments have  shown  that  these  heretofore  obscure 
changes  are  dependent  upon  anatomical  and  physiologi- 
cal peculiarities  of  the  gland.  They  have  shown  that  the 
condition  is  essentially  necrosis  and  not  inflammation. 

The  lesion  known  as  fat  necrosis  was  first  adequately 
described  by  Balser  ^°  in  1882.  Studies  of  Fitz,  Chiari, 
R.  Langerhans,  Hildebrand  and  Dettmer,  and  others, 
have  demonstrated  the  relation  of  fat  necrosis  to  lesions 
of  the  ]Dancreas  and  have  shown  that  the  condition  is 
not  a  disease  sui  generis,  as  many  writers  have  described 
it,  but  a  sequence  of  a  considerable  variety  of  pancreatic 
lesions. 

Clinical  observations  inaugurated  by  Thomas  Cawley 
as  early  as  1788  have  shown  that  diabetes  mellitus  is 
frequently  associated  with  grave  disease  of  the  pancreas, 
but  the  relationship  of  the  pancreas  to  carbohydrate 
metabolism  had  not  been  clearly  recognized  until  Von 
Mering  and  Minkowski  ^  ^  succeeded  in  completely  ex- 
tirpating the  organ  in  dogs.  Their  experiments  demon- 
strate, it  is  well  known,  that  gl^^cosuria  and  other  symp- 
toms characteristic  of  diabetes  follow  this  operation. 
Numerous  observations  made  both  before  and  after  the 
publication  of  these  studies  have  shown  that  diabetes 
mellitus,  in  a  large  proportion  of  cases,  is  associated  with 
disease  of  the  pancreas.  Many  lesions  of  the  organ  are 
unaccompanied  by  glycosuria,  and  numerous  attempts 
have  been  made  to  define  what  pancreatic  lesions  are 

"Balser:  Ueber  Fettnekrose.     VirchoAv's  Arch.,  1882,  xc,  520. 
"  V.    Mering    and    Minkowski :  Diabetes    mellitus   nacb    Pankreas- 
exstirpation.     Arch.  f.  exper.  Path.  u.  Pharni.,  1890,  xxvi,  371. 


viii  PREFACE 

peculiar  to  diabetes.  Accumulating  evidence  obtained 
by  histological  studies  of  the  diseased  organ  has  shown 
that  diabetes  mellitus  accompanies  those  lesions  which 
attack  the  ductless  structures  discovered  by  Langerhans 
and  known  as  the  islands  of  Langerhans.  That  form  of 
diabetes  which  is  referable  to  a  lesion  of  the  pancreas 
may  be  regarded  as  a  symptom  of  destructive  changes 
aff'ecting  these  structures. 

The  development  of  knowledge  of  pancreatic  disease 
can  be  followed  in  the  monographs  of  Fitz,  Korte,^^ 
Oser,^-^  Lancereaux,^*  Mayo  Robson  and  Moynihan,^^ 
Mayo  Robson  and  Cammidge/*^  Truhart/'  and  Lazarus,^'* 
and  in  the  first  edition  of  this  book. 

Increased  knowledge  of  pancreatic  disease  has  aided 
diagnosis,  and  has  materially  enlarged  the  opportunity 
for  successful  surgical  interference.  Since  Bozeman'" 
and  Grussenbauer  ^o  first  described  operations  for  cyst 

"  Korte :  Chirurgische  Krankheiten  des  Pankreas.  Deutsche  Chir- 
urgie,  Stuttgart,  1898. 

^"Oser:  Die  Erkrankungen  des  Pankreas.  Nothnagel's  Spec.  Path, 
und  Ther.,  xvii,  Vienna,  1898. 

"  Lancereaux :  Traite  des  maladies  du  foie  et  du  pancreas,  Paris. 
1899. 

"  Mayo  Robson  and  Moynihan :  Diseases  of  the  Pancreas,  Phila- 
delphia and  London,  1903. 

'"Mayo  Robson  and  Cammidge:  The  Pancreas,  Philadelphia  and 
London,  1907. 

"  Truhart :  Pankreas-Pathologie,  I.  Th.,  Multiple  Abdominale  Fett- 
gewebsnekrose,  Wiesbaden,  1902. 

"  Lazarus :  Beitrag  zur  Pathologic  und  Therapie  des  Pankreas  mil 
besonderer  Beriicksichtigung  der  Cysten  und  Steine,  Berlin,  1904. 

"Bozeman:  Cyst  of  the  Pancreas,  New  York  Med.  Record,  1882, 
xxi,  46. 

'°  Gussenbauer :  Zur  operat.  Behandlung  der  Paiikreascysten.  Arch, 
f.  Chir.,  1883,  xxix,  355. 


PREFACE  ix 

of  the  pancreas,  surgical  treatment  has  been  extended  not 
only  to  cj^sts,  and  in  a  few  instances  to  tumors,  but  to 
the  various  acute  disorders  of  the  organ.  Von  Mikulicz- 
Radecki  (1903)  thus  described  the  status  of  surgical 
diagnosis  and  the  usual  practice  of  surgeons:  ''At  the 
present  time  most  cases  are  operated  upon  when  the 
diagnosis  is  only  probable,  and  only  after  the  abdominal 
cavity  has  been  opened  can  a  differential  diagnosis  be 
made.  As  is  well  known,  in  the  beginning  of  the  era  of 
pancreatic  surgery  most  operations  were  undertaken  on 
a  rule,  when  the  pancreas  is  intact  we  find  other  injuries 
pancreas  is  deemed  probable  it  is  considered  wise  to  sub- 
mit the  patient  to  an  exploratory  laparotomy.  This  prac- 
tice fortunately  is  of  no  great  consequence,  because,  as 
a  rule,  when  the  pancreas  is  intact  we  find  other  injuries 
or  diseases  present  which  justify  laparotomy."  Study 
of  the  pathology  of  the  pancreas,  I  believe,  has  removed 
much  of  this  obscurity  concerning  its  diseases.  In  the 
succeeding  chapters  knowledge  of  the  gland  has  been 
systematically  reviewed  and  the  attempt  has  been  made 
to  elucidate  the  clinical  aspect  of  its  disease  by  the  aid 
of  experimental  and  anatomical  data. 

In  the  first  edition  of  this  book  diseases  dependent 
upon  the  peculiar  physiology  of  the  pancreas,  namely, 
hemorrhagic  necrosis  (acute  hemorrhagic  pancreatitis), 
fat  necrosis,  and  diabetes  mellitus,  received  special  atten- 
tion, whereas  little  space  was  given  to  those  lesions 
which  resemble  similar  changes  of  other  organs.  Dur- 
ing the  past  seven  years  abundant  data  have  been  collected 
by  many  observers  with  the  purpose  of  testing  various 
hypotheses  proposed  to  explain  the  normal  or  diseased 
activity  of  the  gland.     This  wealth  of  material  has  neces- 


X  PREFACE 

sitated  a  systematic  review  of  the  entire  subject,  but 
in  the  present  edition,  as  in  the  first,  detailed  discussion 
has  been  devoted  to  those  conditions  which  are  as  yet 
obscure.  For  this  reason  hemorrhagic  necrosis,  chronic 
pancreatitis,  and  the  pancreatic  pathology  of  diabetes 
mellitus  have  been  described  with  much  detail.  The 
attempt  has  been  made  to  collect  and  classify  those 
observations  which  may  serve  as  a  basis  for  further 
advance  in  the  knowledge  of  pancreatic  disease. 

The  present  work  was  begun  in  1895  in  the  pathologi- 
cal laboratory  of  the  Johns  Hopkins  Plospital  under  the 
direction  of  Dr.  William  H.  Welch.  A  large  part  of  the 
data  described  in  the  following  chapters  has  been  ob- 
tained in  the  pathological  laboratories  of  the  Johns  Hop- 
kins Hospital  and  of  the  Presbyterian  Hospital  of  New 
York.  I  am  indebted  for  additional  material  to  the  kind- 
ness of  Dr.  G.  J.  Adami,  Dr.  C.  W.  Duval,  Dr.  E.  Eliot, 
Dr.  Simon  Flexner,  Dr.  E.  Hodenpyl,  Dr.  Walter  James, 
Dr.  0.  Klotz,  Dr.  F.  Kinnicutt,  Dr.  E.  Libman,  Dr.  War- 
field  Longcope,  Dr.  W.  G.  MacCallum,  Dr.  F.  B.  Mallory, 
Dr.  David  Marine,  Dr.  Charles  Norris,  Dr.  H.  Oertel, 
Dr.  J.  G.  Thacher,  Dr.  F.  C.  Wood,  Dr.  J.  Homer  Wright, 
and  others.  I  have  incorporated  in  the  text  the  results 
of  a  study  of  hemorrhagic  necrosis  of  the  pancreas  made 
in  collaboration  with  Dr.  J.  C.  Meakins.  In  the  chapter 
on  the  pathology  of  the  pancreas  with  diabetes  mellitus 
the  observations  of  Dr.  R.  L.  Cecil  have  been  freely  used. 


CONTENTS 


CHAPTER  PAGE 

Preface v 

History v 

I. — The  Anatomy  of  the  Pancreas 1 

Development  of  the  Pancreas 4 

The  Pancreatic  Ducts 7 

Topography  of  the  Pancreas 17 

Medical  and  Surgical  Anatomy  of  the  Pancreas 22 

Injury  of  the  Pancreas 25 

II. — Anomalies  of  the  Pancreas 29 

Accessory  Pancreas 30 

Diverticula  Caused  by  Anomalies  of  the  Pancreas 44 

III. — Histology  of  the  Pancreas 50 

Pancreatic  Lobule 51 

Ducts  and  Acini 55 

Islands  of  Langerhans 59 

Histogenesis  of  the  Secreting  Acini  and  of  the  Islands  of  Lan- 
gerhans    66 

Function  of  the  Islands  of  Langerhans 69 

IV. — The  Pancreas  and  Digestion , 77 

Pancreatic  Juice  and  its  Enzymes 78 

Disturbances  of  Digestion  Caused  by  Absence  of  Pancreatic 

Juice  in  the  Intestine 87 

Changes  in  the  Urine  Referable  to  Pancreatic  Disease  .......  98 

V. — The  Pancreas  and  Carbohydrate  Metabolism 102 

VI. — Hemorrhagic   Necrosis   of  the   Pancreas   (Acute  Hemor- 
rhagic Pancreatitis) 118 

Etiology 127 

Pathology 158 

Symptoms 164 

Treatment 171 

VII. — Fat  Necrosis 176 

xi 


xii  CONTENTS 

VIII. — Acute  Pancreatitis 200 

IX. — Chronic  Interstitial  Pancreatitis 209 

Varieties  of  Chronic  Pancreatitis 210 

Etiology 224 

Symptoms 243 

X. — Tuberculosis  of  the  Pancreas — Syphilis 249 

Syphilis 250 

XI. — Pancreatic  Calculi 257 

XII.— Cysts 266 

Pathology 266 

Symptoms 281 

Treatment 284 

XIII.— Carcinoma 288 

XIV. — Degenerative  Changes  Affecting  the  Islands  op  Langer- 

HANS 299 

XV. — Pathology  of  the  Pancreas  with  Diabetes  Mellitus 317 

XVI. — Hemochromatosis  and  Bronzed  Diabetes 365 


DISEASE  OF  THE  PANCREAS 

CHAPTER  I. 

THE  ANATOMY  OF  THE  PANCREAS. 

The  pancreas  is  subject  to  greater  variation  in  size 
and  shape  than  other  glandular  organ.  The  ducts 
of  the  gland  vary  widely  in  their  conformation  and  in 
their  relation  to  one  another  and  to  the  common  bile 
duct.  Only  by  a  study  of  many  specimens  is  it  possible 
to  determine  the  relative  frequency  of  anatomical  pecu- 
liarities which  have  a  physiological  significance  and  con- 
stitute an  important  factor  in  the  production  of  certain 
pathological  alterations. 

The  descriptions  of  the  pancreas  given  by  text-books 
of  anatomy  vary  little,  but  I  believe  may  be  so  modified 
as  to  give  a  clearer  conception  of  the  topography  of  the 
gland.  A  few  well-known  facts  may  be  recalled  in  order 
to  make  clear  the  subsequent  description. 

The  right  extremity  of  the  pancreas,  lying  in  the  con- 
cavity of  the  duodenum  and  being  wider  and  thicker  than 
the  remainder  of  the  gland,  is  termed  the  head,  and  forms 
an  enlarged,  somewhat  bulbous,  mass,  the  long  axis  of 
which  makes  an  angle  with  the  remainder  of  the  gland. 
A  constricted  part,  or  neck,  connected  with  the  upper  and 
anterior  aspect  of  the  head,  at  first  directed  slightly 
upward  and  forward,  is  continued  to  the  right  as  the 
body  of  the  gland.  In  contact  with  this  neck,  in  the 
groove  which  causes  its  constriction,  lie  the  superior 
mesenteric  vessels,  which  pass  from  behind  below  the 

1 


2  DISEASE  OF  THE  PANCREAS 

organ,  while  a  short  process  of  the  head  projects  behind 
these  vessels,  thus  deepening  the  groove  in  which  they 
lie.  The  body  terminates  near  the  spleen  in  a  slightly 
tapering  extremity  called  the  tail,  but  no  line  of  demar- 
cation exists  between  these  two  parts.  The  larger  duct 
of  the  gland,  the  duct  of  Wirsung,  traverses  the  organ 
from  left  to  right,  bends  downward  and  backward  in 
the  neck,  and,  approaching  the  posterior  surface  of  the 
head,  finally  reaches  the  wall  of  the  duodenum,  which  it 
penetrates  afer  uniting  with  the  common  bile  duct. 

The  older  writers,  including  Galen,  Vesalius,  and 
Fallopius,  believed  that  the  organ  existed  to  support 
and  protect  more  important  structures  in  contact  with 
it.  The  recognition  of  its  physiological  significance  was 
possible  only  after  the  discovery  of  Wirsung  (1643)  that 
it  is  traversed  by  a  duct  which,  receiving  branches  from 
every  side,  increases  in  size  and  finally  opens  into  the 
duodenum  (Fig.  1). 

Santorini,  however,  first  recognized  that  two  ducts 
are  normally  i^resent;  he  described  and  accurately  pic- 
tured ^  the  smaller  duct,  to  which  his  name  has  been 
given.  According  to  his  description,  it  terminates  in  a 
small  papilla  situated  upon  the  mucous  membrane  of  the 
duodenum  about  two  finger-breadths  nearer  the  stomach 
than  the  large  papilla  in  which  terminates  the  larger 
pancreatic  duct  and  the  common  bile  duct.     Subsequent 

^  Figs.  2  and  6  are  reproduced  from  the  excellent  plates  of  Santo- 
rini, published  in  1775,  thirty-eight  years  after  his  death,  by  Michael 
Girardi,  under  the  title,  "  Jo.  Dominici  Santoiini  anatomici  summi 
septem  deeim  tabulae  quas  nunc  primum  edit  atque  erxplicat  Usque  alias 
addit  de  structura  mammarum  et  de  tunica  testis  vaginali."  For  the 
opportunity  to  reproduce  these  plates  I  am  indebted  to  the  kindness 
of  Dr.  Howard  A.  Kelly,  from  whose  library  this  volume  was  obtained. 


ANATOMY  OF  THE  PANCREAS  S 

anatomists,  including  Meckel  and  Cruveilliier,  thought 
that  the  occurrence  of  an  accessory  duct  was  exceptional, 
but  Claude  Bernard,^  in  his  memoir  upon  the  pancreas, 
described  the  second  smaller  outlet  as  constantly  present. 

*^j!7u'n     cHtctuf     cmusi(nm     cum.  w^ftpkcwiisr  ruv    t-Omu/ir    nru-Ur-    vi  Jcincrealr  a  ^a^cmi' lf'^v;wu> 


aaa-linff  fuvfii'orIiiiicrea(ts- ao   ommjecdont  tUacia- ■  ci      I  at-/  wUf{;nt  daodim- 

Cd-Jifteya  parr  vt/^'ioi' Ao  tltd  nonhvii/ aivuuor ■        h-s^ecJu.^  Vesuce  ttfttntr  w^iw«iMufn.-v'rvfiTfttr ' 


huJJJJi-J  \MnuU  duiclem  c^^eurmi-vimir-juni  voncreArdwem ;  ■]{■  Ortjiciui't. daUuS  nouih'  inwiift 
ti    ■      1/fna     Jt»(enu:,,\  // -         2  circ    fieittf 

J.  J  '   Arierici  Sft^ey^ua  /■''  mw  ■  J^tujt'e/?ur  Tyn/onwrtn /I'rtim-/ 


PaL^)  Cf-^ 


Fig.  1, — The  original  drawing  of  Wirsung,  showing  the  pancreatic  duct.     Reproduced  from 
the  dissertation  of,  Schinnei 

Among  most  mammals  the  adult,  it  is  well  known, 
possesses  two  ducts,  one  of  which  joins  the  common  bile 
duct.  The  pancreas  of  the  cat  and  of  the  dog  consists 
of  two  parts,  an  upper  horizontal  arm  extending  from 
the  duodenum  to  the  spleen  and  a  descending  arm  lying 


^  Claude   Bernard :     Memoire    sur   le   pancreas.      Suppl.    Compt. 
rend,  de  I'Acad.  des  sciences,  1856. 


4  DISEASE  OF  THE  PANCREAS 

in  contact  with  the  duodenum  and  projecting  into  the 
duodenal  mesentery.  In  the  cat  a  large  duct,  sending  out 
branches  into  both  arms  of  the  gland,  enters  the  intestine 
by  a  common  orifice  with  the  bile  duct,  while  a  short 
distance  below  this  orifice  a  much  smaller  duct,  anas- 
tomosing with  the  larger  in  the  substance  of  the  gland, 
enters  the  duodenum.  In  the  dog  the  larger  pancreatic 
duct  enters  the  intestine  several  centimetres  below  the 
smaller,  which  joins  the  common  bile  duct.  Revell''' 
found  considerable  variation  in  the  size  of  the  two  ducts ; 
in  twenty-nine  out  of  thirty  dogs  they  anastomosed 
within  the  gland  and  in  three  animals  the  condition  was 
exceptional,  the  two  ducts  having  approximately  the  same 
size.  In  the  rabbit,  of  which  the  pancreas  consists  of 
lobules  scattered  in  the  mesentery,  a  large  duct  enters 
the  intestine  below  the  bile  duct,  while  the  smaller  duct 
is  so  atrophied  that  it  is  almost  impermeable. 

DEVELOPMENT  OF  THE  PANCREAS. 

With  an  increased  knowledge  of  the  development  of 
the  gland,  peculiarities  of  the  ducts  have  been  better 
understood.  Earlier  investigations  have  seemed  to  show 
that  the  development  of  the  organ  varies  greatly  among 
different  classes  of  vertebrates,  but  more  careful  obser- 
vations have  disclosed  considerable  uniformity. 

The  occurrence  of  a  single  dorsal  and  two  ventral 
outgrowths  has  been  described  in  various  species  of  fish 
(Laguesse,*  Hammar,^  Stohr,*'  and  Goppert'),  in  am- 

'Revell:  American  Jour,  of  Anat.,  1902,  i,  443. 

*  Laguesse :  Bibliogr.  Anat.,  1894,  ii,  101. 

'Hamniar:  Arch.  f.  Anat.  u.  Phys.,  Anat.  Abt.,  1893,  123. 

"  Stohr :  Anat.  Anz.,  1893,  viii,  205. 

'  Goppert :  Morph.  Jalirb.,  1891,  xvii,  100. 


^Wur 


Fig.  2. — P^eproduction  of  the  original  drawing  of  Santorini,  showing  both  ducts  of  the  pancreas. 


ANATOMY  OF  THE  PANCREAS  5 

phibia  (Gotte,^  Goppert,  and  Felix  9),  and  in  reptiles 
(Brachet  ^^),  though  an  occasional  observer  has  found 
only  one  ventral  outgrowth. 

Stoss^^  has  carefully  described  the  development  of 
the  pancreas  in  a  mammal  (the  sheep).  The  bud-like 
outgrowth  from  which  the  liver  develops  is  formed  at  a 


Fig  3. — Development  of  the  pancreas  in  the  sheep.  D,  duodenum;  Pd,  dorsal 
"anlage"  of )  the  pancreas;  Pv,  ventral  "anlage"  of  the  pancreas;  Dc,  ductus  choledo- 
chus;  GB  gall-bladder;  V,  umbilical  vein;  Vp,  portal  vein.  (After  Stoss,  slightly  modified.) 

time  when  the  gastro-intestinal  tract  is  a  straight  tube 
attached  by  its  mesentery  to  the  posterior  abdominal 
wall.  The  pancreas  makes  its  appearance  as  a  projection 
(Fig.  3,  i.,  Pd)  upon  the  dorsal  surface  of  the  intestine 
between  the  liver  and  the  stomach,  which  is  now  repre- 
sented by  a  spindle-shaped  dilatation  of  the  intestinal 


'  Gotte :    Die  Entwickelungsgeschichte  der  Unke,  Leipzig,  1875. 
Felix:  Arch.  f.  Anat.  u.  Phys.,  1892.     Anat.  Abt.,  281. 
Brachet :  Jonr.  de  I'anat.  et  de  la  phys.,  1896,  xxxii,  620. 
Stoss :  Inaug.  Diss.,  Ledpzig,  1892 ;  and  Auat.  Anz.,  1891,  vi,  666. 


6  DISEASE  OF  THE  PANCREAS 

tube.  Upon  the  ventral  surface  of  the  intestine,  at  either 
side  of  the  hepatic  duct,  appear  two  diverticula  (Fig. 
3,  ii.,  Pv),  which  later  fuse  to  form  the  ventral  rudiment 
of  the  pancreas  and  subsequently  grow  to  meet  the  dorsal 
part  (Fig.  4). 

The  stomach  at  first  lies  in  the  median  plane  of  the 
body,  and  that  part  which  is  to  become  the  greater  curva- 
ture is  now  the  posterior  or  dorsal  border  of  the  organ 
(Fig.  5).  The  alteration  of  position  by  which  the  stom- 
ach is  transversely  placed,  the  posterior  wall  becoming 
the  inferior  border  or  greater  curvature,  is  accompanied 
by  a  corresponding  change  in  the  position  of  the  duode- 
num and  pancreas.  The  dorsal  part  of  the  pancreas, 
which  has  pushed  its  way  into  the  dorsal  mesentery  of 
the  intestinal  tube,  comes  to  lie  transversely  with  its 
left  extremity  near  the  spleen,  and  at  the  same  time,  as 
Stoss  has  shown,  that  part  of  the  duodenum  to  which 
the  pancreas  and  liver  are  attached  twists  upon  its  longi- 
tudinal axis  in  such  a  way  that  the  ventral  wall,  and  with 
it  the  openings  of  the  bile  duct  and  ventral  pancreatic 
outgrowth,  passes  to  the  right  and  backward  (Fig.  3,  v.), 
becoming  the  posterior  wall  of  the  duodenum.  With 
further  growth  the  part  of  the  pancreas  which  was  orig- 
inally ventral  comes  into  contact  with  the  larger  dorsal 
part  of  the  organ.  The  two  parts  unite  to  form  a  con- 
glomerate organ  and  the  two  ducts,  which  were  at  first 
separate,  anastomose.  At  an  early  stage  the  duct  of 
the  dorsal  part  atrophies,  and  finally  disappears,  so  that 
the  single  opening  which  remains  in  the  adult  sheep  is 
that  of  the  ventral  outgrowth. 

The  development  of  the  human  pancreas,  according 
to  most  recent  observations,  does  not  differ  from  that 


p.hep. 


^^  .  V-. -*««=^  j)_panc.v.--'  ,j^^  ja 
]  'anc.  d: 


\ — D.cysi. 


^D.panc.d. 

■D.chol. 


Fig.  4. — Fusion  of  the  dorsal  and  ventral  pancreas  in  a  human  embryo  13. G  mm.  in    length. 
(After  Thyng,  American  Jour,  of  Anat.,  1908,  vii,  499.) 


Future  diaphragm 


Anterior  mesentery 
(falciform  ligament)  /    /   y 

Liver — /    / 


Anterior  mesentery 
(gastro-hepatic  omentum) 


Umbilical  vein 
Body-cavity 


Connection  of 
vitelline  sialic 


Beginning  of  large  intestine 


Stomach 

Spleen 

Mesogastrium 

Coeliac  axis 
Pancreas 

Duodenum 

.Superior  mesen- 
teric artery 

Mesenterium 
commune 


mesenteric  artery 
Allantoic  duct 
Cloaca 


Fig.  5. — Diagram  showing  intestinal  canal  and  mesenterv  in  the  sixth  week  of  fetal  life.     (.Piersol.)     (After 

Mall  and  Toldt.) 


"4 


i  / 


.:*<3«5' 


^' 


Fig.  0. — Reproduction  of  a  drawing  by  Santorini,  pul)lished  by  tiirardi  in  1775.  The 
diiodenum'lias  Ijeen  opened,  and  botli  the  bile  papilla  and  papilla  of  the  smaller  pancreatic  duct 
are  e.\posed. 


ANATOMY  OF  THE  PANCREAS  7 

of  other  vertebrates.  Earlier  observers,  Pliisalix/^  Zim- 
rcermann,^^  and  Hamburger/*  and  more  recently, 
Volker,^^  and  Tliyng,  ^^  have  described  two  primitive  out- 
growths. Felix,  Jankilowitz  ^"  (in  an  embryo  of  47  mm.) 
and  Von  Brunn^^  have,  however,  found  three  ''anlage," 
a  dorsal  and  a  right  and  a  rudimentary  left  ventral,  the 
two  latter  subsequently  fusing.  The  dorsal  rudiment, 
arising  between  the  bile  duct  and  the  stomach,  forms  the 
ductus  Santorini,  the  ventral  the  ductus  pancreaticus 
(Wirsungi).  In  an  embryo  six  weeks  old  Hamburger 
has  found  the  dorsal  and  ventral  parts  of  the  gland 
united,  and  concludes  that  anastomosis  occurs  during 
the  second  half  of  the  second  month  of  embryonic  life. 

THE  PANCREATIC  DUCTS. 

Variation  of  the  Pancreatic  Ducts. — Such  embryo- 
logical  study  has  shown  that  the  greater  part  of  the 
pancreas, — namely,  the  body  and  tail  and  part  of  the 
head, — develops  from  the  primitive  dorsal  outgrowth, 
represented  in  the  adult  by  the  ductus  pancreaticus  acces- 
sorius  (Santorini),  which  enters  the  duodenum  in  between 
the  bile  papilla  and  the  stomach  (Fig.  6).  The  ductus 
pancreaticus  (WirSungi)  enters  the  duodenum  in  common 
with  the  ductus  choledochus  below  the  duct  of  Santorini — 
that  is,  at  a  point  further  from  the  stomach — and  in  the 

"  Phisalix :  Compt.  rend,  de  I'Acad.  des  sciences,  1887,  civ,  799 ; 
Arch.  zool.  Exper.,  1888,  s.  2,  vi,  279. 

"  Zimmermann :  Anat.  Anz.,  1889,  iv,  Suppl.,  139. 
"Hamburger:  Anat  Anz.,  1892,  vii,  707. 
"Volker:    Arch.   f.   mik.   Anat.,   1902,   lix,   62. 
"Thyng-:  American  Jour,  of  Anat.,  1908,  vii,  489. 
"  Jankilowitz :  Inaug.  Di&s.,  Berlin,  1895. 
'*Von  Brunn:    Anat.  Hefte,  1894,  Abt.  ii,  iv,  87. 


8  DISEASE  OF  THE  PANCREAS 

head  of  the  gland  represents  the  primitive  ventral  out- 
growth. The  two  ducts  usually  anastomose  at  an  early 
period.  The  part  of  the  upper  or  originally  dorsal  duct 
which  lies  between  the  duodenal  orifice  and  its  anas- 
tomosis with  the  lower  duct  undergoes  partial  atrophy, 
and  the  lower  channel  increasing  in  size  appears  to  be  a 
continuation  of  the  large  duct,  which,  derived  from  the 
dorsal  outgrowth,  follows  the  axis  of  the  gland.  Hence 
the  duct  of  Wirsung,  which  affords  an  outlet  for  almost 
the  entire  pancreatic  secretion,  is  derived,  in  the  head 
of  the  gland,  from  the  ventral  pancreas  and  in  the  body, 
from  the  dorsal. 

In  a  few  individuals  the  upper  duct  or  duct  of  San- 
torini  remains  larger  than  the  lower;  in  other  instances 
there  is  no  anastomosis  between  the  two  ducts.  Claude 
Bernard,  Henle,^^  Sappey,^*'  and  other  anatomists  have 
described  various  modifications  to  which  the  ducts  are 
subject.  Increased  importance  has  been  given  to  the 
relationship  of  the  pancreatic  ducts  to  one  another  and 
to  the  common  bile  ducts  by  the  study  of  pathological 
lesions  dependent  upon  anatomical  peculiarities  of  these 
ducts. 

Schirmer  -^  examined  the  pancreatic  ducts  in  one  hun- 
dred and  four  bodies  and  tested  their  patency.  He 
exposed  the  larger  duct  in  the  body  of  the  gland  and, 
inserting  a  cannula,  forced  air  in  the  direction  of  the 
duodenum,  which  had  been  previously  opened.  By  keep- 
ing the  specimens  under  water,  the  escape  of  air  from 

'"Henle:  Handbuch  der  Anatomie  des  Menschen,  Braunschweig. 
1873,  ii. 

'"  Sappey :  Traite  d'anatomie,  Paris,  1S89,  iv. 
"  Schirmer,  Inaug.  Diss.,  Basel,  1893. 


ANATOMY  OF  THE  PANCREAS  9 

one  or  both  ducts  was  determined.  The  ducts  were  later 
carefully  dissected.  Schirmer  described  numerous  varie- 
ties dependent  upon  the  relative  size  of  the  two  ducts, 
their  anastomosis  within  the  gland,  their  patency,  and 
their  relation  to  the  bile  duct.  He  attempted  no  classifi- 
cation of  the  diverse  forms,  but  for  the  sake  of  clearness 
they  may  be  collected  into  three  groups,  as  follows : 

Ducts  in  anastomosis  and  patent: 

Duct  of  Wirsung  larger 60 

Duct  of  Santorini  larger 6 

Ducts  in  anastomosis;  one  wholly  or  partially  oblit- 
erated : 

Papilla  of  duct  of  Santorini  not  patent 24 

Duct  of  Wirsung  absent 5 

Ducts  not  in  anastomosis: 

Duct  of  Wirsung  larger 5 

Duct  of  Santorini  larger 4 

I  have  dissected  the  pancreatic  ducts  in  one  hundred 
specimens.  In  order  to  determine  their  patency  and, 
if  possible,  the  existence  of  an  anastomosis  between  them, 
a  solution  of  Berlin  blue  was  injected  into  the  duct  of 
AVirsung,  exposed  by  transverse  section  of  the  body  of 
the  gland.  To  avoid  extravasation  the  injection  was 
made  at  a  pressure  little  greater  than  that  of  a  column 
of  water  two  feet  in  height.  By  compressing  that  orifice, 
from  which  the  fluid  readily  escaped,  the  attempt  was 
made  to  divert  the  flow  to  a  second  orifice.  Such  speci- 
mens were  hardened  in  formalin  and  subsequently  pre- 
served in  alcohol;  the  disvsection  of  the  ducts  was  facili- 
tated by  the  presence  of  the  injected  material.  In  those 
instances  in  which  the  lesser  papilla   appeared  to  be 


10  DISEASE  OF  THE  PANCREAS 

closed,  serial  sections  were  made  in  order  to  more  accur- 
ately determine  its  patency. 

My  observations  differ  in  several  respects  from  those 
of  Schirmer.  Though  the  ducts  vary  much  in  their  rela- 
tive size  and  one  has  at  times  undergone  partial  oblitera- 
tion, two  are  constantly  present.  In  twelve  instances 
Schirmer  found  that  the  common  bile  duct  joined  the 
upper  pancreatic  duct,  while  further  from  the  stomach 
was  a  second  smaller  papilla.  His  observation  is  diffi- 
cult to  explain,  for  in  my  specimens  the  relationship  of 
the  lower  duct, — the  duct  of  "VYirsung, — to  the  common 
bile  duct  is  constant  and  agrees  with  the  well-established 
embryological  development  of  the  two  ducts. 

The  varieties  of  the  pancreatic  ducts  and  their  rela- 
tive frequency  among  one  hundred  specimens  which  I 
have  examined  are  indicated  in  the  following  classifi- 
cation : 

I.  Ducts  in  anastomosis: 

(1)  Duct  of  Wirsung  larger. 

(a)   Duct  of  Santorini  patent 63 

(6)   Duct  of  Santorini  not  patent 21 

(2)  Duct  of  Santorini  lai-ger  or  equal  in  size  to  the 

duet  of  Wirsung. 

(a)   Duct  of  Wirsung  patent G 

(6)   Duet  of  Wii^sung  not  patent 0 

II.  Ducts  not  in  anastomosis  : 

(1)  Duet  of  Wirsung  larger 5 

(2)  Duet  of  Santorini  larger 5 

In  considerably  more  than  one-half  the  specimens 
both  ducts  are  patent,  and  the  duct  of  Wirsung,  which 
unites  with  the  duct  of  Santorini,  is  larger  than  the  latter 
(Fig.  6,  i.) ;  the  duct  of  Santorini  diminishes  in  size  as 


ANATOMY  OF  THE  PANCREAS         11 

it  approaches  the  duodenum,  and  opens  upon  the  lesser 
papilla  by  a  narrow  orifice.  Eeceiving  numerous 
branches  from  the  head  of  the  gland,  and  gradually  in- 
creasing in  size  as  the  duct  of  Wirsung  is  approached, 
the  duct  of  Santorini  appears  to  be  a  branch  of  the  larger 
duct,  into  which,  in  the  majority  of  instances,  it  doubtless 
pours  its  secretion.  In  only  forty-eight  instances  has  it 
been  possible  to  inject  fluid  at  a  low  pressure  through 
the  smaller  papilla.  In  some  of  these  specimens  the  in- 
jected fluid  has  escaped  readily,  and  hence  it  is  probable 
that  the  duct  may  occasionally  act  as  a  functional  outlet. 
In  fifteen  specimens  the  patency  of  the  duct  has  been 
demonstrated  only  by  microscopic  examination  of  serial 
sections  through  the  lesser  papilla,  while  in  a  very  large 
group  of  cases  it  has  not  been  possible  even  by  that  means 
to  demonstrate  its  patency.  Hence  in  more  than  half 
of  all  individuals  the  lesser  duct  is  at  its  orifice  obliter- 
ated or  so  constricted  that  it  cannot  assume  the  function 
of  the  larger  duct  when  occluded. 

Occasionally  the  duct  of  Santorini  enters  the  upper 
aspect  of  the  duct  of  Wirsung  (Fig.  7,  i.) ;  at  times  it 
arises  from  the  lower  aspect  (Fig.  8,  i.,  ii.),  and  by  a 
somewhat  tortuous  course  reaches  the  upper  papilla.  The 
point  at  which  the  anastomosis  occurs  varies  consider- 
ably, and  though  usually  several  centimetres  from  the 
termination  of  both  ducts,  may  be  less  than  a  centimetre 
from  the  duodenal  orifice  of  one,  the  other  duct  then  fol- 
lowing a  tortuous  course  to  reach  its  termination  (Fig. 
8,  iii.,  iv.).  Occasionally  the  duct  of  Santorini  appears 
to  be  a  direct  continuation  of  the  main  channel  within 
the  body  of  the  gland  (Fig.  8,  iv.),  thus  suggesting  the 
original  embryonic  condition. 


12 


DISEASE  OF  THE  PANCREAS 


In  ten  cases  (as  in  Fig.  7,  v.,  vi.,  vii.)  no  anastomosis 
has  been  found  between  the  two  ducts.  In  four  addi- 
tional cases,  included  in  Group  I,  of  the  table  (see  Fig. 
7,  iii.),  the  duct  of  Santorini  is  almost  wholly  indepen- 


Fig.  7. — Varying  relations  of  the  duct  of  Santorini  (s)  to  the  duct  of  Wirsung  {w).    Drawn 
from  dissected  specimens. 

dent  of  the  duct  of  Wirsung,  with  which  it  is  united 
only  by  a  narrow  twig.  Receiving  branches  from  all 
sides  and  gradually  increasing  in  size  as  it  approaches 
the  duodenum,  the  duct  of  Santorini  in  such  case  repre- 
sents the  outlet  for  a  part  of  gland  substance  and  is 


ANATOMY  OF  THE  PANCREAS 


13 


functionally  independent  of  the  lower  duct,  even  though 
this  small  communicating  twig  unites  them.  Indeed,  it 
is  conceivable  that  when  the  two  ducts  appear  to  be 
wholly  independent  a  very  minute  communication,  though 
present,  has  not  been  demonstrated. 

The  relative  diameter  of  the  two  ducts  varies  much. 
When  thev  anastomose,  in  only  seven  of  ninety  cases  is 


Fig.  8. — Varying  relations  of  the  duct  of  Santorini  (s)  to  the  duct  of  Wirsung  (w).    Broken 
lines  are  in  the  plane  of  the  interlobular  fissure.     Drawn  from  dissected  specimens. 

the  duct  of  Santorini  equal  or  larger  (Fig.  7,  iv.),  but 
of  ten  cases  in  which  there  is  no  anastomosis,  in  half  the 
specimens  the  duct  of  Santorini  equals  or  exceeds  the 
duct  of  Wirsung  (Fig.  7,  vii.). 

The  Diverticulum  of  Vater. — Embryological  study  has 
shown  that  the  ventral  pancreatic  outgrowth  of  the  in- 
testine arises  in  contact  with  the  hepatic  duct,  while  the 
dorsal  bud,  arising  at  an  earlier  period,  is  situated  be- 


14  DISEASE  OF  THE  PANCREAS 

tween  the  hepatic  duct  and  what  will  subsequently 
become  the  stomach.  In  accordance  with  this  arrange- 
ment the  lower  pancreatic  duct — the  duct  of  Wirsung — 
in  all  the  specimens  which  I  have  examined,  approaches 
the  intestine  beside  the  bile  duct,  while  the  duct  of 
Santorini  enters  the  intestine  above  it. 

The  ductus  choledochus  and  the  duct  of  Wirsung 
penetrate  side  by  side  the  coats  of  the  duodenum  through 
which  they  pass  obliquely  a  distance  of  about  2  cm.  and 
end  in  a  papilla-like  elevation  of  the  mucous  membrane. 
Within  the  papilla  they  unite  to  form  a  short  common 
cavity — the  diverticulum  of  Vater.  At  the  point  where 
the  common  duct  enters  the  wall  of  the  intestine  it  is  con- 
stricted, or  at  least  but  little  distensible,  so  that  gall- 
stones often  lodge  in  this  situation. 

The  descriptions  of  the  diverticulum  or  ampulla  of 
Vater  given  by  different  anatomists  do  not  vary  materi- 
ally. It  may  be  described  as  a  conical  cavity  into  the 
base  of  wliich  open  the  two  ducts;  the  apex  situated  at 
the  summit  of  the  diverticulum  is  their  common  duodenal 
orifice.  According  to  Testut  ^^  its  length  varies  from  G 
to  7  mm.,  according  to  Sappey  from  7  to  8  mm.  Occasion- 
ally the  two  ducts  have  no  common  channel  but  open  by 
separate  orifices  upon  the  summit  of  the  bile  papilla. 
Claude  Bernard  described  a  mode  of  termination  which 
has  since  been  observed  by  others.  The  bile  duct  is  pro- 
longed as  far  as  the  mucosa  of  the  duodenum,  ujDon  which 
it  opens  by  a  circular  orifice.  The  terminal  part  of  the 
pancreatic  duct,  like  a  gutter,  embraces  the  bile  duct, 
and  its  orifice  has  the  outline  of  a  crescent. 


^Testut:  Traite  d'anatomie  huniaiiie,  Paris,  1894,  iii. 


ANATOMY  OF  THE  PANCREAS         15 

The  orifice  of  the  diverticulum  of  Vater  constitutes 
the  narrowest  part  of  the  biliary  channel,  and  here  small 
calculi  not  infrequently  become  impacted.  A  small  stone 
lodged  in  the  diverticulum  may  occlude  its  duodenal 
orifice,  and,  too  small  to  completely  fill  the  diverticulum 
and  occlude  the  two  ducts  that  enter  it,  may  convert  the 
latter  into  a  single  closed  channel  along  which  bile  may 
be  forced  by  the  gall-bladder  (Fig.  9,  i.).  Bile  thus 
injected  into  the  pancreatic  duct  causes,  as  will  be  subse- 
quently shown,  the  condition  known  as  acute  hemorrhagic 
pancreatitis.     This  lesion  does  not  commonly  follow  the 


ae 


f 


di^ 


Fig.  9. — Diagram  showing,  i.,  diverticulum  of  Vater  containing  a  calculus;   ii.,  common 
bile  duct  {dc.)  and  duct  of  Wirsung  {dw)  entering  intestine  separately. 

expulsion  of  a  gall-stone  from  the  common  duct.  For 
its  production  it  is  necessary  that  the  diverticulum  of 
Vater  be  capacious,  with  a  length  at  least  greater  than 
the  diameter  of  its  duodenal  orifice. 

With  these  facts  in  view,  the  length  of  the  diverticu- 
lum has  been  measured  in  one  hundred  specimens ;  vary- 
ing from  zero  to  11  mm.,  it  averages  only  3.9  mm.  In 
eleven  instances  the  two  ducts  open  separately  at  the 
summit  of  the  bile  papilla  and  no  diverticulum  exists 
(Fig.  9,  ii.).  In  only  thirty  instances  does  the  length  of 
the  diverticulum  reach  5  mm. 


16  DISEASE  OF  THE  PANCREAS 

In  seventy-five  of  these  specimens  the  diameter  of  the 
duodenal  orifice  has  been  measured  after  the  insertion 
of  probes  of  varying  size.  The  average  diameter  of  the 
orifice  is  2.5  mm.  In  twenty-one  instances  the  diameter 
of  the  orifice  is  equal  to  or  greater  than  the  length  of  the 
diverticulum;  and  it  is  obviously  impossible  that  a  cal- 
culus, assuming  it  to  be  approximately  spherical  and 
lodged  in  the  orifice,  could  only  partially  occlude  the 
cavity. 

Termination  of  the  Duct  of  Santorini. — The  termina- 
tion of  the  duct  of  Santorini  is  represented  upon  the 
mucosa  of  the  duodenum  by  an  elevated  papilla  situated 
at  a  variable  distance  above  the  common  orifice  of  the 
duct  of  Wirsung  and  the  bile  duct  (see  Fig.  6).  Though 
often  small  and  inconspicuous,  it  is  recognized  in  all  the 
specimens  which  I  have  examined;  in  one  case  it  is  so 
small  that  it  has  been  found  only  after  examination  of 
serial  sections  through  the  mucosa  opposite  the  point  at 
which  the  duct  of  Santorini  reached  the  intestinal  wall. 
The  papilla  varies  considerably  in  size  and  shape,  being 
at  times  a  small,  nipple-like  projection,  at  times  a  low, 
broad  elevation.  Within  the  papilla  the  duct  of  San- 
torini usually  becomes  very  narrow  and  is  not  infre- 
quently wholly  obliterated.  In  serial  sections  it  is  foimd 
irregular  in  outline,  provided  with  many  lateral  diver- 
ticula, and  often  very  tortuous. 

Much  difficulty  has  been  encountered  in  determining 
the  frequency  with  which  the  smaller  papilla  is  patent. 
On  the  one  hand  a  small  quantity  of  mucus  within  the 
minute  lumen  may  readily  prevent  the  penetration  of 
injected  material,  and,  on  the  other  hand,  Henle  states, 
material    injected    under    considerable    pressure    may 


ANATOMY  OF  THE  PANCREAS         17 

produce  a  false  passage.  By  injecting  air  into  the  duct 
Schirmer  was  unable  to  demonstrate  its  patency  in 
twenty-one  of  one  hundred  and  four  specimens.  Helly  ^^ 
has  more  recently  made  a  careful  microscopical  study  of 
the  duct  of  Santorini  as  it  penetrates  the  intestine,  and 
in  ten  of  fifty  specimens  found  it  obliterated. 

In  a  considerable  number  of  the  specimens  which  I 
have  examined  it  has  not  been  possible  to  force  from  the 
lesser  papilla  fluid  injected  under  low  pressure  into  the 
duct  exposed  by  cutting  across  the  body  of  the  gland. 
AVhere  by  such  gross  examination  the  patency  of  the  duct 
of  Santorini  has  not  been  demonstrated,  serial  sections 
have  been  made  through  the  papilla,  and  in  twenty-one 
instances  the  lumen  of  the  duct  has  not  been  demonstra- 
bly continuous  with  that  of  the  intestine.  Penetrating 
the  muscularis  of  the  intestine  and  passing  by  a  tortuous 
course  a  variable  distance  into  the  papilla,  the  duct, 
beset  with  many  lateral  diverticula,  ends  a  short  distance 
below  the  mucosa ;  the  lumen  of  the  duct  or  one  or  more 
of  its  diverticula  approach  the  mucosa,  below  which  there 
is  occasionally  a  minute  dilatation. 

TOPOGRAPHY  OF  THE  PANCREAS. 

Relation  of  the  Parenchyma  to  the  Ducts. — The  pan- 
creas consists,  it  is  well  known,  of  lobules  held  together 
by  connective  tissue.  Upon  the  surface  of  the  gland 
polygonal  areas  varying  greatly  in  size  and  shape  are 
mapped  out  by  clefts  filled  with  very  loose  areolar  tissue. 
By  carefully  dissecting  the  loose  tissue  which  these  clefts 
contain  the  gland  may  be  divided  into  well-defined  masses 

'■^  Helly :  Arch,  f .  mik.  Anat.,  1898,  lii,  773. 
2 


18  DISEASE  OF  THE  PANCREAS 

of  parencliyiTia,  the  shape  of  which  is  dependent  upon 
imitua]  pressure.  Such  lobules  are  usually  a  centimetre 
or  more  across,  and  in  the  body  and  tail  are  frequently 
oblong  with  a  long  diameter  at  right  angles  to  the  axis 
of  the  gland;  in  the  head  they  are  more  irregular  in 
shape.  These  relatively  large  glandular  masses,  sepa- 
rated by  loose  connective  tissue,  are  found  to  be  further 
divided  by  more  inconspicuous  and  less  well-defined  septa 
into  smaller  lobules  of  varying  size  and  shape,  usually 
several  millimetres  across.  Microscopic  examination 
demonstrates  that  these  are  again  divisible  into  even 
smaller  ill-defined  areas,  which  may  be  designated  pri- 
mary lobules ;  the  larger  masses  may  be  named  secondary 
lobules;  whereas  the  largest  bodies,  separated  by  loose 
areolar  tissue,  may  be  conveniently  termed  tertiary 
lobules. 

The  large  pancreatic  duct,  as  it  passes  through  the 
body  of  the  gland,  is  closely  beset  with  lateral  branches, 
which  are  most  numerous  upon  its  superior  and  inferior 
aspects  and  usually  make  an  oblique  angle  with  the  main 
channel.  These  branches  frequentlj^  divide,  and  from 
a  branch  and  its  subdivisions  are  given  off  lateral  twigs 
which  penetrate  the  tertiary  lobules.  In  some  instances 
the  duct  of  the  tertiary  lobule  may  enter  directly  the  duct 
of  AVirsung.  In  attempting  to  separate  the  lobules  by 
breaking  through  the  loose  tissue  which  unites  them  it  is 
usually  found  that  the  interlobular  clefts  or  septa  do  not 
reach  the  ducts  upon  which  the  tertiary  lobules  are  situ- 
ated, but  the  boundaries  of  the  latter  are  partially  ob- 
scured by  secondary  lobules  in  intimate  contact  with 
the  wall  of  the  duct  and  directly  tributary  to  it. 

In  the  head  of  the  gland  tertiary  lobules  preserve  a 


ANATOMY  OF  THE  PANCREAS         19 

similar  relationship  to  the  two  ducts  present  in  this  part 
of  the  gland  and  are  tributary  to  branches  or  sub- 
branches  of  the  duct  of  Wirsung  or  of  the  duct  of  San- 
torini.  A  large  branch  (Fig.  7,  i.  and  ii.,  x)  of  the  duct  of 
Santorini  usually  passes  downward  and  drains  a  large 
part  of  the  head,  while  a  similar  branch  (Fig.  7,  i.  and  ii. 
y)  from  the  duct  of  Wirsung  near  its  junction  with  the 
duct  of  Santorini,  passing  downward  and  to  the  left, 
usually  enters  the  projection    (Fig.   10,   z/)    which  lies 


Fig.  10. — Diagrammatic  drawing  of  the  pancreas,  showing  the  two  lobes  which  form 
the  head.  The  interlobular  fissure  has  been  opened  by  dissection,  and  the  lower  part  (x) 
of  the  lobe  corresponding  to  the  duct  of  Santorini  has  been  drawn  upward  in  order  to  ex- 
pose the  lobe  corresponding  to  the  duct  of  Wirsung. 

behind  the  superior  mesenteric  vessels.  From  that  part 
of  the  duct  of  Wirsung  which  lies  in  the  head  of  the 
pancreas  branches  are  usually  small  and  enter  without 
subdivision  the  tertiary  lobules. 

As  the  result  of  the  arrangement  just  described  the 
head  of  the  gland  consists  of  two  distinct  sets  of  lobules 
grouped  about  the  two  ducts,  and  by  careful  dissection, 
more  readily  in  hardened  specimens,  the  relation  of  the 
parenchyma  to  the  two  ducts  may  be  demonstrated.  The 
two  groups  of  lobules  belonging  to  the  two  ducts  are 
separated  near  the  duodenum  by  loose  areolar  tissue, 
while  at  the  point  where  these  ducts  anastomose  they  are 


20  DISEASE  OF  THE  PANCREAS 

united.  The  head  of  the  pancreas  (Fig.  10)  is  in  fact 
composed  of  two  distinct  lobes,  which  for  the  sake  of  con- 
venience may  be  designated  the  anterior  lobe  of  the  head 
(about  the  duct  of  Santorini)  and  the  posterior  lobe  of 
the  head  (about  the  duct  of  Wirsung).  These  lobes  are 
separated  by  an  interlobular  fissure  or  cleft  lying  midway 
between  the  two  ducts.  The  anterior  lobe,  represented 
as  drawn  upward  in  the  figure,  is  larger  than  the  pos- 
terior lobe,  which  lies  behind  it,  and,  being  much  wider 
from  above  down,  forms  the  lower  or  descending  part 
of  the  head  (Fig.  10,  x).  The  posterior  lobe  is  a  rela- 
tively narrow  compressed  mass  of  parenchyma,  flattened 
anteroposteriorly  and  surrounding  on  all  sides  the  duct 
of  Wirsung;  a  projection  (Fig.  10,  y),  before  mentioned, 
usually  passes  from  its  upper  and  left  aspect  behind  the 
superior  mesenteric  vessels. 

The  two  lobes  are  firmly  attached  to  the  duodenum 
in  the  neighborhood  of  their  respective  ducts,  but  be- 
tween the  ducts  each  lobe  is  readily  separable  from  the 
intestine.  The  interlobular  fissure  where  it  is  in  contact 
with  the  duodenum  lies  midway  between  the  two  ducts  in 
a  direction  from  above  downward  and  slightly  forward, 
and  extends  into  the  substance  of  the  head  a  variable 
distance,  often  four  to  five  cm.,  its  depth  being  dependent 
upon  the  distance  from  the  duodenum  at  which  the  two 
ducts  anastomose.  Where  anastomosis  has  occurred 
near  the  orifice  of  one  duct  (Fig.  8,  iii.  and  iv.),  the  other 
duct  lengthening  during  the  course  of  subsequent  develop- 
ment  becomes  much  bowed,  and  with  it  the  correspondin'?: 
lobe,  so  that  the  interlobular  fissure  can  be  followed 
between  adjacent  surfaces  of  the  lobe,  which  is,  as  it 
were,  folded  upon  itself. 


ANATOMY  OF  THE  PANCREAS         21 

After  breaking  through  the  loose  tissue  filling  the 
fissure,  adjacent  surfaces  of  the  two  lobes  are  found  to 
be  relatively  smooth  and  to  resemble  the  external  surface 
of  the  organ.  Within  the  fissure  are  contained  branches 
of  the  pancreaticoduodenal  artery  and  vein.  The  com- 
mon bile  duct  usually  lies  along  the  upper  border  of  the 
posterior  lobe  of  the  head  of  the  pancreas,  and  the  inter- 
lobular cleft  meets  the  upper  surface  of  the  gland  along 
a  line  in  front  and  to  the  left  of  this  duct.  In  order  to 
expose  the  fissure,  the  bile  duct  may  be  used  as  a 
landmark. 

Relation  of  the  Common  Bile  Duct  to  the  Head  of  the 
Pancreas. — Study  of  the  diseases  of  the  liver  and  of  the 
pancreas  has  given  considerable  importance  to  the  ana- 
tomical relationship  of  the  bile  duct  to  the  pancreas  and 
its  ducts.  The  common  bile  duct  descends  toward  the 
duodenum  alongside  the  head  of  the  pancreas,  occasion- 
ally embedded  in  its  substance,  and  comes  in  contact  with 
the  duct  of  Wirsung,  beside  which  it  lies  for  a  short  but 
variable  distance  before  entering  the  wall  of  the  intestine. 

Helly  has  carefully  studied  the  relation  of  the  bile 
duct  to  the  head  of  the  pancreas  in  forty  subjects.  The 
lower  part  of  the  duct  for  a  distance  varying  from  two 
to  seven  centimetres  is  in  contact  with  the  head  of  the 
pancreas,  or,  as  I  have  shown,  with  its  posterior  lobe. 
In  fifteen  instances  (37.5  per  cent.)  the  duct  lies  in  a 
groove  upon  the  surface  of  the  gland  often  converted  into 
a  canal  by  the  adjacent  duodenum.  In  the  remaining 
twenty-five  instances  (62.5  per  cent.)  the  duct  is  com- 
pletely surrounded  for  a  varying  distance  by  pancreatic 
tissue. 


22  DISEASE  OF  THE  PANCREAS 

MEDICAL  AND   SURGICAL  ANATOMY   OF  THE   PANCREAS. 

Blood-Vessels. — Blood  is  supplied  to  the  splenic  part 
of  the  pancreas  by  the  coeliac  axis  through  its  branch  the 
splenic  artery,  which  is  in  contact  with  the  upper  edge  of 
the  gland ;  to  the  head  of  the  pancreas  by  the  coeliac  axis 
through  the  superior  pancreaticoduodenal,  a  branch  of 
the  hepatic  artery,  and  by  the  superior  mesenteric  artery 
through  the  inferior  pancreaticoduodenal  artery.  The 
posterior  and  inferior  pancreaticoduodenal  arteries 
anastomose,  and  lying  in  contact  with  pancreas  and  duo- 
denum supply  both  organs  with  blood. 

Occlusion  of  the  arteries  supplying  both  pancreas  and 
duodenum  causes  gangrene  of  the  latter.  Kronlein  ^^ 
has  described  a  case  in  which  gangrene  of  the  colon  has 
followed  removal  of  carcinoma  of  the  pancreas,  and  has 
shown  that  gangrene  may  be  the  result  of  ligation  of  the 
median  colic  artery  when,  as  in  a  small  proportion  of 
individuals,  it  arises  from  the  superior  mesenteric  near 
the  pancreas. 

Venous  blood  from  the  pancreas  enters  the  portal  sys- 
tem in  great  part  through  numerous  branches  of  the 
splenic  vein  and  in  less  quantity  through  branches  of  the 
superior  mesenteric  vein.  The  splenic  vein  is  in  intimate 
contact  with  tlie  posterior  surface  of  the  pancreas,  and 
not  infrequently  undergoes  injur^^  with  subsequent 
thrombosis  as  a  result  of  lesions  of  the  pancreas,  espe- 
cially hemorrhagic  necrosis;  with  suppuration  in  the 
pancreas  multiple  abscesses  in  the  liver  may  be  caused 
by  infected  emboli. 

Anatomical  Relation  of  the  Pancreas   to  Adjacent 

"  Kronlein :  Beit.  z.  klin.  Chir.,  1895,  xiv,  663. 


Apex  suprarenahs 
(gl  dcxtrse  ) 


V  portse 


Glandula  snprarenalis  (sinistra) 

,Ren  (sinister) 


Lien 


Ren  (dexter)  - 


]'ars  descend- 
uns  duodeni 


2Sl Pancreas 


-Colon 
trans- 
versum 


A.  mesenterica  superior 
Fig.  11. — Relations  of  the  pancreas.     (After  His.)     (Barker's  Laboratory  Manual  of  Anatomy.) 


Ren  (dexter) 


V.  cava  inf.  Aorta  RotropaTicroatic  "  faseia  (if  fusion  " 

Ren  (sinister) 


Paries  abdom- 
inis 


Hepar 


Ductus 
choledoclius 


Lien 


nil  us  lienis 

IJk-  frastro- 

lienale 
I^ig.  jilireiiico- 
lienale 


V.  portie 
A.  hepat.  prop- 

A.  hepatic  a 


Lig.  teres  liepatis 

Omentum  minus 
Lig.  faleiforme  liepatis 


Vciitrieulus 


Ca^um  peritoniei 


Corpus  pancreatis 
Vestibulum  bursic  omentalis 


Fig.  12. — Transver.se  section  passing  through  the  bursa  omentalis  at  the  level  of  the  foiamcn  epiploicuin 
VVin.slowi.      (After  Poirier  and  Charp.v.)      f  Marker's  Lalioratory  Manual  of  Anatomy.) 


ANATOMY  OF  THE  PANCREAS         23 

Organs. — The  head  of  the  pancreas  lying  within  the  duo- 
denal loop  (Fig.  11)  overlies  the  aorta  and  inferior  vena 
cava  and  is  firmly  attached  to  the  tissues  in  front  of 
the  vertebral  column.  The  tail  of  the  pancreas  is  less 
immovably  attached  and  occasionally  lies  within  the 
transverse  mesocolon,  so  that  tumors  arising  from  this 
part  of  the  gland  may  have  a  limited  mobility.  The  an- 
terior surface  of  the  organ  is  covered  by  peritoneum, 
which  forms  the  posterior  wall  of  the  lesser  peritoneal 
cavity  (Fig.  12).  Acute  inflammation  of  the  pancreas  is 
frequently  transmitted  to  the  overlying  peritoneum  and 
peritonitis,  usually  limited  to  the  lesser  peritoneal  cavity, 
follows.  Closure  of  the  foramen  of  Winslow  by  inflam- 
matory adhesions  allows  the  accumulation  of  exudate 
within  the  cavity  of  the  lesser  peritoneum.  Blood  or 
exudate  within  this  cavity  and  overlying  the  pancreas 
may  cause  physical  signs  not  distinguishable  from  those 
of  tumors  {e.g.,  cyst)  situated  within  the  substance  of 
the  gland. 

The  pancreas  is  covered  by  liver,  stomach,  and  trans- 
verse colon.  Korte  -^  examined  thirty  cadavers  in  order 
to  determine  the  relation  of  the  pancreas  to  the  adjacent 
organs  after  the  abdomen  had  been  opened.  In  twenty 
bodies  the  gland  was  completely  covered  by  these  organs, 
but  in  ten  subjects  some  part  of  the  gland  was  covered 
only  by  omentum.  In  six  instances  the  head  of  the  pan- 
creas was  exposed  between  the  edge  of  the  liver  and  the 
colon,  which  was  found  depressed.  The  pancreas  was 
twice  exposed  by  a  cleft  between  the  right  and  left  lobes 

'■"Korte:  Die  chirurgischen  Krankheiten  des  Pankreas.  Deutsche 
Cbirurgie,  Stuttgart,  1898. 


24  DISEASE  OF  THE  PANCREAS 

of  the  liver;  once  it  was  exposed  below  the  level  of  the 
pylorus  and  once  above  the  lesser  curvature  of  the 
stomach.  In  the  two  remaining  bodies  the  pancreas, 
lying  behind  the  gastrohepatic  omentum,  could  be  seen 
and  felt  through  a  space  between  the  edge  of  the  liver 
and  the  lesser  curvature  of  the  stomach;  this  relation- 
ship, which  occurs  with  gastroptosis,  explains  why  cysts 
arising  from  the  head  of  the  gland  occasionally  present 
above  the  lesser  curvature  of  the  stomach.  In  a  case 
recently  observed  at  autopsy  in  the  Presbyterian  Hos- 
pital, New  York,  dilatation  of  the  stomach  accompanying 
ulceration  and  constriction  of  the  pylorus  was  accom- 
panied by  such  advanced  gastroptosis  that  the  entire 
head  and  half  of  the  body  of  the  pancreas  lay  exposed 
above  the  lesser  curvature  of  the  stomach. 

Anatomical  Facts  of  Surgical  Import. — Cysts  and 
solid  tumors  of  the  tail  are  more  readily  extirpated  than 
those  situated  in  other  parts  of  the  gland,  for  they  are 
in  less  intimate  contact  with  vital  structures,  and  the  tail 
of  the  gland  serves  as  a  pedicle.  Section  and  closure  of 
the  pancreatic  duct  is  followed  by  chronic  inflammation 
of  the  parenchyma  tributary  to  the  occluded  duct ;  conse- 
quently the  resulting  injury  to  the  gland  is  greatest  when 
section  is  nearest  to  the  duodenum. 

Access  to  the  pancreas  at  operation  is  obtained  by 
several  routes : 

(a)  The  gland  is  usually  exposed  through  the  gastro- 
colic ligament,  the  lesser  peritoneal  cavity  being  entered 
between  the  stomach  and  transverse  colon. 

(b)  When  the  stomach  has  sunk  downward  and  the 
pancreatic  lesion,  usually  a  cyst  or  an  abscess,  is  situated 
near  the  upper  border  of  the  head  of  the  gland,  access 


ANATOMY  OF  THE  PANCREAS         25 

may  be  possible  between  liver  and  stomach  through  the 
gastrohepatic  omentum. 

(c)  When  cysts  which  arise  from  the  tail  of  the  pan- 
creas occupy  the  transverse  mesocolon  the  lesion  may  be 
reached  through  the  lower  layer  of  the  mesocolon  after 
the  colon  has  been  pushed  upward,  blood-vessels  being 
carefully  avoided. 

(d)  The  pancreas  may  be  reached  through  the  lumbar 
region  without  opening  of  the  peritoneal  cavity.  (1) 
Abscesses  have  been  opened  through  the  left  lumbar  re- 
gion, and  since  they  tend  to  sink  in  this  direction  efficient 
drainage  may  be  thus  secured  in  some  instances.  (2) 
A  cyst  projecting  from  the  head  of  the  pancreas  to  the 
right  side  has  been  opened  through  the  right  lumbar 
region. 

INJURY  OF  THE  PANCREAS. 

Since  the  pancreas  is  almost  completely  covered  by 
the  liver,  stomach,  and  colon,  and  is  in  contact  with 
other  important  structures,  injury  to  the  gland  uncompli- 
cated by  more  serious  injury  to  other  organs  is  infre- 
quent. In  most  instances  laceration  of  the  pancreas  is 
associated  with  grave  injury  to  the  liver,  stomach,  spleen, 
kidney,  or  intestine.  The  observations  of  Korte  previ- 
ously cited  suggest  the  occasional  possibility  of  injury 
almost  wholly  limited  to  the  gland,  and  in  a  few  instances 
the  gland  has  been  crushed  against  the  vertebral  column 
by  force  applied  over  the  epigastrium.  The  passage  of 
a  wheel  across  the  abdomen  or  compression  between  the 
buffers  of  two  cars  has  ruptured  the  gland.  In  children 
the  ribs  are  soft  and  may  yield  to  pressure,  but  in  adults 
they  are  usually  broken  before  the  pancreas  is  crushed. 


26  DISEASE  OF  THE  PANCREAS 

Injury  to  the  pancreas  has  been  observed  with  relative 
frequency  in  boys. 

A  sharply  localized  blow, — for  example,  the  kick  of 
a  horse  or  a  blow  from  the  fist, — has  been  the  most  fre- 
quent cause  of  localized  pancreatic  injury.  Uncompli- 
cated injury  to  the  pancreas  in  a  case  described  by  Jaun^*^ 
was  caused  by  an  unusual  form  of  assault.  A  Hindoo 
was  severely  beaten  and  kicked  after  his  hands  had  been 
tied  together  and  his  knees  pinned  in  front  of  the  abdo- 
men by  a  lath  between  bended  knees  and  elbows.  In  a 
case  of  Wagstaff,^'  a  fall  from  a  cart  upon  the  left  side, 
was  followed  after  two  days  by  vomiting ;  on  the  fourth 
day  death  occurred,  and  although  there  was  no  other 
abdominal  injury  the  pancreas  was  torn  across.  In  the 
case  of  Wilks  and  Moxon,^^  uncomplicated  injury  to  the 
pancreas  was  caused  by  the  wheel  of  a  wagon. 

Injury  of  sufficient  severity  to  affect  the  pancreas 
is  in  most  instances  immediately  followed  by  shock  and 
collapse,  but  appearance  of  such  symptoms  may  be  de- 
layed. Complete  absence  of  external  evidence  of  injury 
has  been  observed  with  severe  contusion  of  the  pancreas. 

Accumulation  of  blood  in  the  lesser  peritoneal  cavity 
raay  be  recognizable  after  injury.  A  workman  was  in- 
jured by  a  heavy  chest  which  fell  upon  his  left  side  and 
forced  him  against  a  post ;  immediately  after  the  injury 
Kraske  found  dulness  in  the  lower  jjart  of  the  abdomen 
on  the  right  side.     On  the  sixth  day  there  were  symptoms 

""Jaun:  Indian  Ann.  of  Med.  Sci.,  1855,  iii,  721.  Quoted  by 
Leith,  Lancet,  1895,  ii,  770. 

"  Wa^staff :  Lancet,  1895,  i,  404. 

"^  Wilks  and  Moxon :  Pathological  Anatomy,  3d  ed.,  p.  491. 
Quoted  by  Leith. 


ANATOMY  OF  THE  PANCREAS  27 

of  renewed  hemorrhage  and  dulness  appeared  below  the 
stomach.  Death  occurred  on  the  next  day;  autopsy 
showed  blood  in  the  lesser  peritoneal  cavity  and  complete 
rupture  of  the  pancreas  opposite  the  vertebral  column. 
Immediately  after  the  injury  blood  doubtless  passed 
through  the  foramen  of  Winslow,  but  subsequent  closure 
by  adhesions  caused  accumulation  in  the  lesser  peritoneal 
cavity. 

The  following  case  reported  by  Eandall  '^^  illustrates 
the  possibility  of  recovery  after  operation  performed  for 
the  relief  of  pancreatic  injury: 

A  man,  42  years  of  age,  one  hour  after  a  meal,  while  walking 
backward  leading  his  horses  was  hit  in  the  epigastrium  by  the  pole  of 
his  van  and  was  forced  against  a  second  stationary  wagon.  Violent 
pain,  collapse,  and  vomiting  followed  almost  immediately,  and  an 
hour  later  his  pulse  was  small  and  weak  and  temperature  95°  F. 
There  was  a  painful  bruise  midway  between  the  ensiform  cartilage  and 
umbilicus  and  well-marked  dulness  in  the  right  flank.  At  operation 
six  houre  after  injury  much  fluid  and  clotted  blood  was  found  in  the 
peritoneal  cavity;  the  hepatogastric  ligament  was  torn,  and  an  oblique 
tear  through  the  body  of  the  pancreas  exposed  a  tongue  of  glandular 
tissue,  at  its  base  half  the  width  of  the  organ.  This  rent  was  closed 
by  four  silk  stitches  and  the  opening  in  the  hepatogastric  ligament 
was  closed  by  a  continuous  suture  of  catgut,  space  being  left  for  drain- 
age with  gauze.  Blood  was  removed  from  the  peritoneal  cavity.  Dur- 
ing three  days  following  operation  there  was  much  vomiting  and  on 
one  occasion  collapse.  Abundant  turbid  viscid  fluid  was  discharged 
from  the  wound  and  there  was  excoriation  of  the  surrounding  skin. 
Ointment  was  applied.  The  fluid  which  escaped  became  whitish  and 
was  so  abundant  that  it  spurted  from  the  wound  when  the  patient 
coughed.  The  discharge  became  watery  and  diminished  m  amount  and 
seven  weeks  after  injury  ceased  completely.     The  sinus  closed  almost 

^  Randall :  Lancet,  1905,  i,  291. 


28  DISEASE  OF  THE  PANCREAS 

immediately  and  the  patient  left  the  hospital  a  month  later.  Sugar 
was  found  on  only  one  occasion  four  weeks  after  injury.  There  was 
emaciation  but  after  the  fistula  had  healed  weight  was  rapidly  regained. 

The  case  illustrates  the  healing  of  a  pancreatic  wound, 
the  occurrence  of  pancreatic  fistula  with  excoriation  of 
the  skin,  and  si3ontaneous  closure  of  the  fistulous  tract. 
The  treatment  of  pancreatic  fistula  is  described  in 
Chapter  XII. 

The  relation  of  hemorrhagic  necrosis  of  the  pancreas 
(hemorrhagic  and  gangrenous  pancreatitis)  to  fat  ne- 
crosis, and  of  pancreatic  cyst  to  injury  of  the  pancreas, 
will  be  discussed  in  subsequent  chapters. 


CHAPTER  II. 


ANOMALIES    OF    THE    PANCREAS. 


Since  the  ducts  of  the  pancreas  are  subject  to  great 
variation,  it  is  not  surprising  that  the  gland  presents 
anomalies  dependent  upon  alterations  of  the  usual  proc- 
ess of  development.  Malformations  have  been  described, 
particularly  by  earlier  writers.  The  tail  of  the  gland 
has  occasionally^  been  bifid.  The  absence  of  lobules  of 
parenchyma  about  the  duct  of  Wirsung  or  its  branches 
for  a  short  distance  has  caused  a  division  of  the  gland 
into  two  parts;  this  anomaly,  due  to  impaired  develop- 
ment, according  to  Hyrtl,  at  points  where  large  blood- 
vessels,— namely,  the  superior  mesenteric  or  the  left 
gastro-epiploic  arteries, — are  in  contact  with  the  gland, 
has  been  designated  pancreas  diviswn  and  should  not  be 
identified  with  true  accessory  pancreas. 

Annular  Pancreas. — Of  greater  importance  is  the 
anomaly  known  as  annular  pancreas,  of  which  several 
instances  were  described  years  ago  by  Tiedemann,  Be- 
court,  Moyse,  and  Ecker  (cited  by  Schirmer),  while  more 
recently  similar  cases  have  been  recorded  by  Symington,^ 
Generisch,^  and  Tieken.^  The  head  of  the  pancreas  com- 
pletely surrounds  the  duodenum  and  may  cause  a  partial 
constriction  of  the  lumen.  In  a  case  described  by  Gener- 
isch  the  lumen  of  the  duodenum  was  so  constricted  that 
the  tip  of  the  thumb  could  with  difficulty  be  introduced 

^  Symington :    Jour,  of  Anat.  and  Phys.,  1885,  xix,  292. 
^Generisch:    Verhandl.  d.  intemat.  med.  Cong.,  1890,  ii,  140. 
'  Tieken  :  American  Med.,  1901,  ii,  826. 

29 


30  DISEASE  OF  THE  PANCREAS 

at  the  site  of  the  constricting  glandular  tissue,  whereas 
the  duodenum  above  the  constriction  was  dilated  to  the 
size  of  the  large  intestine ;  the  stomach  was  dilated,  and 
its  wall  was  hypertrophied.  Generisch  had  seen  three 
specimens  in  which  the  head  of  the  pancreas  almost  com- 
pletely surrounded  the  duodenum,  leaving  uncovered  only 
a  finger-breath  of  the  duodenal  circumference;  the  duo- 
denum was  somewhat  constricted  and  the  stomach 
dilated.  In  the  case  described  by  Tieken  the  descending 
part  of  the  duodenum  was  constricted  by  a  ring  of  pan- 
creatic tissue  and  its  lumen  admitted  only  the  tip  of  the 
index  finder.  The  duodenum  above  the  stricture  was 
dilated  to  nearly  half  the  size  of  the  stomach,  but  though 
the  muscular  coat  of  the  stomach  was  hypertrophied  the 
viscus  was  not  dilated.  The  patient,  who  died  with  acute 
endocarditis,  had  exhibited  no  symptoms  of  gastro- 
intestinal disease. 

ACCESSORY  PANCREAS. 

A  true  accessory  pancreas  is  a  mass  of  i^ancreatic 
tissue  wholly  separated  from  the  pancreas  and  provided 
with  a  duct  of  its  own.  Such  isolated  masses  of  glan 
dular  tissue  derive  some  importance  from  the  possi- 
bility that  they  may  perhaps  vicariously  assume  the 
function  of  the  main  organ  when  it  is  diseased  and  that 
they  may  cause  diverticula  or  herniae  of  the  intestinal 
wall.  Klob^  first  demonstrated  the  existence  of  such 
isolated  masses  of  pancreatic  tissue  and  described  two 
examples  of  this  anomaly.  In  one  instance  a  small  flat- 
tened glandular  mass  was  embedded  in  the  wall  of  the 
stomach,  near  the  mid-part  of  its  greater  curvature;  in 

'Klob:  Zeit.  d.  Gesellschaft  d.  Aerzte  zu  Wien,  LS59,  No.  46,  p. 
732. 


ANOMALIES  OF  THE  PANCREAS  31 

the  second  case  a  similar  tiimor-like  body  occupied  the 
wall  of  the  jejunum  four  inches  from  the  duodenum. 
Zenker  ^  subsequently  collected  six  examples  of  the 
anomaly,  and  in  every  instance  demonstrated  the  exist- 
ence of  a  duct  entering  the  intestine  through  the  over- 
lying mucosa. 

In  ten  among  eighteen  hundred  autopsies  performed 
in  the  Johns  Hopkins  Hospital  one  or  more  accessory 
pancreatic  glands  have  been  found.  They  present  feat- 
ures which  I  believe  explain  their  development,  and  for 
this  reason  are  described  with  some  detail.  For  the 
sake  of  convenience  they  may  be  divided  into  two  groups, 
— those  situated  above  the  pancreas  in  the  stomach  and 
duodenum  and  those  below  the  gland  in  the  duodenum 
and  jejunum. 

Accessory  Gland  above  the  Pancreas. 

Specimen  I. — Accessory  pancreas  of  the  stomach  in  a  white  man, 
aged  forty  years.  Near  the  lesser  curvature  of  the  stomach,  8  cm. 
from  the  pylorus,  is  a  firm  flattened  nodule,  1.2  cm.  across,  lying  below 
the  mucosa.  Microscopic  examination  shows  a  compact  mass  of  pan- 
creatic tissue  situated  in  the  submucosa,  extending  into  the  muscularis, 
and  distorting  the  muscle  bundles.  Between  the  lobules,  and  at  times 
within  them,  connective  tissue  is  abundant. 

Specimen  II. — Accessory  pancreas  of  the  stomach  ui  a  colored 
boy,  aged  eleven  years.  Below  the  mucous  membrane  of  the  stomach, 
2  em.  from  the  pylorus,  is  a  firm  nodule  5  mm.  in  diameter.  Microscopic 
examination  shows  a  small  mass  of  pancreatic  tissue  situated  in  the 
submucosa.  Fibrous  stroma  is  more  abundant  between  the  lobules  than 
in  the  normal  gland. 

Specimen  III. — xiberrant  pancreas  of  the  pylorus  in  a  woman, 
aged  sixty-five  yeai^.  At  the  site  of  the  pyloric  valve  of  the  stomach, 
projecting  into  the  lumen,  is  an  elevation  of  the  mucosa,  caused,  as 
microscopic  examination  shows,  by  a  nodule  of  pancreatic  tissue  situ- 

'  Zenker :  Virchow's  Arch.,  1S61,  xxi,  369. 


32  DISEASE  OF  THE  PANCREAS 

ated  in  the  submucosa;  in  the  sections  examined  are  found  two  islands 
of  Langerhans.  Dilated  ducts  are  present,  and  are  most  numerous 
near  the  muscularis.  In  the  underlying  muscle  of  the  pylon;s  is  found 
a  group  of  small  ducts,  while  immediately  below  the  serosa  are  on  sec- 
tion two  widely  dilated,  duct-like  channels  lined  by  high  coluninal  cells. 

Specimen  IV. — Accessory  pancreas  of  the  stomach  and  nodule  of 
the  pylorus  containing  dilated  duets  in  a  white  man,  aged  seventy-three 
years.  In  the  wall  of  the  stomach,  8  cm.  from  the  pylorus,  is  a  nodule, 
2  cm.  across.  At  the  pylorus  is  a  second  nodule-like  projection  of  the 
mucosa,  about  7  mm.  across;  but  here  on  section  no  gland-like  tissue 
is  found.  Examination  of  the  pancreas  demonstrates  the  existence  of 
two  ducts,  of  which  the  duct  of  Santorini  is  smaller  and  terminates 
in  a  small  papilla.  At  the  site  of  the  bile  papilla  is  a  short  diverticulum 
of  the  mucous  membrane.  Microscopic  examination  of  the  gastric 
nodules  shows,  partly  in  the  submucosa  but  chiefly  in  the  muscularis, 
pancreatic  lobules,  often  separated  by  much  interstitial  tissue.  Islands 
of  Langerhans  are  fairly  abundant,  and  ducts,  often  with  wide  lumina, 
occur  throughout  the  section.  The  papillary  projection  at  the  pyloii;s 
is  produced  by  an  increase  in  the  thickness  of  the  submucosa,  where, 
surrounded  by  a  quantity  of  connective  tissue,  is  found  a  duct-like 
structure  identical  in  appearance  with  the  ducts  of  the  pancreatic 
nodule.  In  the  underlying  muscle  of  the  pyloinis  several  ducts  of 
larger  size  are  cut  across,  while  immediately  below  the  serosa  the  section 
cuts  twice  what  appears  to  be  a  dilated  tortuous  duct. 

Specimen  V. — Aberrant  pancreas  (1)  of  the  stomach  and  (2) 
of  the  duodenum^  together  with  pancreatic  tissue  in  the  lesser  papilla 
in  a  white  boy,  aged  four  years.  Immediately  below  the  mucous  mem- 
brane of  the  stomach,  only  2  mm.  from  the  pyloric  orifice,  is  a  nodule 
of  gland-like  tissue  3  mm.  across.  Below  the  mucosa  of  the  duodenum, 
9.5  cm.  below  the  pyloras,  is  a  second  nodule  of  similar  character,  about 
7  mm.  across.  The  papilla  of  the  duct  of  Santorini  is  represented  by 
a  hemispherical  elevation,  7  mm.  across,  which  on  section  appears  to 
contain  a  third  isolated  nodule  of  glandular  tissue.  Microscopic  ex- 
amination shows  that  the  nodule  of  pancreatic  tissue  situated  in  the 
submucosa  of  the  stomach  has  been  the  seat  of  moderate  chronic  inter- 
stitial inflammation,  and  its  ducts,  which  converge  towards  its  under 
surface,    are   dilated   and   contain    polynuclear   leucocytes;   islands   of 


ANOMALIES  OF  THE  PANCREAS  33 

Langerhans  occur.  The  duodenal  nodule  immediately  below  the  pyloruis 
consists  of  pancreatic  tissue  situated  in  the  submucosa  and  muscularis, 
of  which  the  bundles  are  split  apart  and  distorted.  It  projects  beyond 
the  muscle  upon  the  outer  surface  of  the  intestine.  Ducts  and  islands 
of  Langerhans  oceui\  In  the  submucosa,  immediately  above  the  duct 
of  Santorini,  after  it  has  penetrated  the  muscularis  of  the  duodenum, 
is  situated  a  third  nodule  of  pancreatic  substance. 

Specimen  VI. — Aberrant  pancreas  in  the  ivall  of  the  duodenum 
together  with  pancreatic  tissue  in  the  lesser  papilla.  The  mucous  mem- 
brane of  the  duodenum,  4  cm.  above  the  papilla  of  the  duct  of  Santo- 
rini, presents  a  low  elevation  7  mm.  across.  The  papilla  of  the  duct 
is  represented  by  a  low,  broad  elevation  5  mm.  across;  the  duct  of 
Santorini,  smaller  than  the  duct  of  Wirsung,  .-joins  the  latter  and  is 
patent  throughout.  The  nodular  elevation  of  the  duodenum  is  by  micro- 
scopic examination  shown  to  be  caused  by  numerous  pancreatic  lobules 
situated  between  separated  bundles  of  the  muscularis.  A  few  nodules 
which  are  the  seat  of  chronic  interstitial  inflammation  are  situated  in 
the  submucosa,  and  a  tortuous  duct  can  be  traced  to  the  surface  of 
the  mucosa.  The  lesser  papilla  of  the  pancreas  is  found  to  contain 
a  few  nodules  of  pancreatic  tissue  which  has  undergone  chronic  inter- 
stitial inflammation. 

Specimen  VII. — Aberrant  pancreas  of  the  duodenum  in  a  woman, 
aged  fifty-six  yeai^.  Pi-ojecting  upon  the  external  surface  of  the  duode- 
num, between  the  stomach  and  the  pancreas,  is  a  hemispherical  nodule 
8  mm.  across.  On  microscopic  examination  the  main  mass  of  the 
nodule  is  found  to  project  outside  the  muscular  coats,  which  axe  split 
apart  and  over  a  considerable  area  broken  through,  so  that  the  nodule 
is  continuous  with  a  smaller  collection  of  pancreatic  lobules  which  have 
undergone  chronic  interstitial  inflammation  and  are  situated  in  the 
submucosa.     Duets  are  present  and  islands  of  Langerhans  occur. 

Accessory  Gland  below  the  Pancreas. 

Specimen  VIII. — Accessory  pancreas  of  the  duodenum  in  a  white 

woman,  aged  forty  years.     A  small  nodule  of  grayish-yellow  tissue  is 

situated  in  the  wall  of  the  duodenum  below  the  pancreas.     Microscopic 

examination  shows  that  a  mass  of  pancreatic  tissue  is  situated  in  the 

3 


34  DISEASE  OF  THE  PANCREAS 

submucosa,  and  extending  through  the  circular  muscle  coat,  separates 
the  latter*  from  the  longitudinal  layer.  Dense  stroma  surrounds  and 
often  invades  the  gland  lobules.  Ducts  lined  by  columnar  epithelium 
occur. 

Specimen  IX. — Accessory  pancreas  of  the  jejunum  showing  ad- 
vanced chronic  interstitial  inflammation  and  pancreatic  tissue  in  the 
bile  papilla  in  a  colored  woman,  aged  fifty-nine  years.  In  the  jejunum, 
111  cm.  below  the  duodenum  and  opposite  the  mesenteric  attachment, 
is  an  oval  nodule  1,5  em.  across.  It  is  composed  of  firm  grayish  tissue 
and  contains  minute  cysts.  Microscopically  the  tissue  resembles  at 
first  sight  a  small  adenoma.  Embedded  in  dense  fibrous  stroma  are 
groups  of  gland-like  structures  formed  by  high  columnar  cells  sur- 
rounding a  wide  lumen.  In  the  centre  of  each  group  are  one  or  more 
larger  ducts  and  embedded  in  the  dense  stroma  occur  glandular  acini, 
which  contain  centro-acinar  cells.  The  main  mass  of  the  nodule,  which 
has  undergone  advanced  chronic  intestinal  inflammation,  is  situated  in 
the  submucosa,  but  bundles  of  the  underlying  circular  muscle  are 
separated  and  distorted  by  the  presence  of  dilated  ducts.  The  duct  of 
Wirsung  of  the  pancreas  is  much  smaller  than  the  duct  of  Santorini, 
and  does  not  anastomose  with  it.  The  bile  papilla  is  of  very  large  size, 
and  examined  microscopically  is  found  to  contain  lobules  of  pancreatic 
tissue.  They  surround  the  duct  before  it  enters  the  diverticulum  of 
Vater,  which  is  only  2.5  mm.  in  length. 

Specimen  X. — Accessory  pancreas  of  the  jejunum  showing  ad- 
vanced chronic  interstitial  inflammation  a/nd  resembling  a  small  adenoma 
in  a  white  man,  aged  thirty-eight  years.  In  the  jejunum,  four  metres 
from  the  stomach,  is  a  nodule  1  cm.  across.  Microscopic  examination 
shows  numerous  ducts,  isolated  or  surrounded  by  mucous  glands  and 
identical  in  appearance  with  those  of  the  pancreas;  they  are  embedded 
in  abundant  dense  fibrous  stroma.  The  microscopic  appearance  agrees 
with  that  of  Specimen  IX,  save  that  lobules  of  pancreatic  acini  are  no 
longer  preserved.     The  nodule  is  situated  wholly  in  the  submucosa. 

Small  masses  of  aberrant  pancreatic  tissue  are  usually 
about   one   centimetre  in   diameter.     Glinski®   has   de- 


Glinski :  Virchow's  Arch,  1901,  clxiv,  132. 


ANOMALIES  OF  THE  PANCREAS  35 

scribed  an  accessory  gland  of  larger  size;  a  nodule  4.5 
by  3.5  centimetres  across  and  one  centimetre  in  thickness 
was  situated  in  the  muscular  coat  of  the  stomach  near  the 
pylorus.  More  than  one  accessory  gland  may  occur  in 
the  same  individual.  Zenker  found  two  accessory  bodies 
in  the  jejunum,  one  sixteen,  the  other  forty-eight  centi- 
metres below  the  duodenum.  In  Specimen  IV  of  the 
present  series  there  is  an  accessory  pancreas  in  the 
gastric  wall,  and  a  second  nodule  situated  at  the  pylorus 
contains  only  dilated  ducts  but  doubtless  represents  a 
second  isolated  remnant  of  pancreatic  tissue;  in  Speci- 
men V  two  bodies  occur,  one  in  the  stomach,  the  other  in 
the  duodenum,  and  the  papilla  of  the  duct  of  Santorini 
contains  a  third  nodule  of  pancreatic  tissue. 

Accessory  pancreas  is  not  uncommon;  no  available 
statistics  indicate  the  frequency  with  which  the  anomaly 
occurs.  In  five  of  two  hundred  autopsies  LetuUe  found 
aberrant  glands  and  described  a  sixth  case  in  which  a 
partially  isolated  mass  of  pancreatic  tissue  formed  part 
of  the  head  of  the  pancreas.  The  ten  specimens  which  I 
have  described  have  been  collected,  as  I  have  stated,  from 
eighteen  hundred  autopsies. 

Accessory  pancreas  may  occur  above  the  pancreas  in 
the  wall  of  the  stomach,  and  of  the  duodenum  or  with 
about  the  same  frequency  below  the  pancreas  in  the  wall 
of  the  duodenum,  of  the  jejunum  and  even  of  the  ileum. 
Zenker  found  an  accessory  pancreas  54  cm.  from  the 
ileocaBcal  valve.  Approximately  one-third  of  the  aber- 
rant glands  which  have  been  described  have  been  situated 
in  the  wall  of  the  stomach,  usually  near  the  pylorus ;  the 
remaining  two-thirds  have  occurred  in  the  intestinal  wall. 


36  DISEASE  OF  THE  PANCREAS 

Wright"^  has  described  an  unique  example  of  the 
anomaly.  A  child  twelve  years  of  age  had  suffered  with 
a  congenital  umbilical  fistula  which  caused  discomfort  by 
discharge  of  moisture.  After  unsuccessful  attempt  to 
close  the  fistula  the  fistulous  tract  was  removed  and 
within  the  tissue  was  embedded  a  nodule  3.5  millimetres 
in  diameter,  composed  of  glandular  acini  identical  with 
those  of  the  pancreas  and  containing  readily  recognizable 
islands  of  Langerhans.  The  peritoneal  cavity  was 
opened  and  explored  with  the  finger  but  no  connection 
between  fistula  and  intestine  was  found.  The  operation 
was  entirely  successful. 

The  situation  of  the  accessory  pancreatic  tissue  with 
relation  to  the  coats  of  the  intestine  varies.  The  nodule 
is  usually  situated  in  the  muscularis  of  which  the  muscle 
bundles  are  separated  and  distorted  by  the  presence  of 
pancreatic  lobules  and  groups  of  lobules,  and,  it  will  be 
shown  later,  the  muscular  coat  may  be  much  weakened 
by  the  presence  of  the  glandular  tissue.  Three  of  the 
aberrant  glands  which  I  have  observed  have  been  situated 
wholly  in  the  submucosa,  and  in  four  additional  instances, 
though  no  glandular  lobules  have  been  present  in  the 
underlying  muscle  layer,  ducts  have  been  found  here. 
The  five  remaining  accessory  glands  have  occupied  the 
muscular  layer. 

ThoreP  has  found  in  the  mesentery  of  the  upper 
third  of  the  duodenum  an  accessory  pancreatic  nodule 
1  cm.  in  thickness;  three  finger-breadths  distant  in  the 
wall  of  the  jejunum  was  a  second  accessory  pancreas. 

'  Wrij^ht :  Jour,  of  the  Boston  Soc.  of  Med.  Sciences,  1901,  v,  497. 
'Thorel:  Virchow's  Arch.,  1903,  elxxiii,  281. 


ANOMALIES  OF  THE  PANCREAS  37 

In  the  fat  of  the  great  omentum  about  a  hand-breadth 
below  the  greater  curvature  of  the  stomach  Warthin  ® 
found  an  accessory  pancreatic  nodule  8  mm.  in  diameter, 
and  a  duct  was  traced  in  serial  sections  to  a  small  cavity 
about  which  were  foci  of  fat  necrosis ;  he  suggests  that  a 
second  duct  found  in  the  adjacent  omental  fat  has  per- 
haps joined  the  nodule  with  the  stomach. 

The  tissue  of  the  aberrant  gland  does  not  differ  in  its 
histological  features  from  that  of  the  pancreas.  Numer- 
ous ducts  occur,  and  unite  to  open  upon  the  intestinal 
mucosa.  Within  the  acini  are  found  centro-acinar  cells. 
LetuUe  ^^  states  that  the  peculiar  bodies  known  as  islands 
of  Langerhans  do  not  occur  in  the  accessory  gland. 
Wright  has,  however,  demonstrated  their  presence  in  a 
pancreatic  nodule  removed  from  the  neighborhood  of  the 
umbilicus,  and  in  five  of  my  cases  they  have  been  found. 

Pathological  Changes  Affecting  Accessory  Pancreatic 
Tissue. — In  a  case  described  by  Warthin  fat  necrosis  had 
occurred  about  an  aberrant  pancreatic  nodule  and  its 
duct,  which  was  situated  in  the  omentum  near  the  greater 
curvature  of  the  stomach. 

The  isolated  nodule  of  pancreatic  tissue  tends  to 
undergo  chronic  interstitial  inflammation  and  interstitial 
tissue  is  almost  constantly  present  in  greater  quantity 
than  in  the  normal  gland.  Inflammatory  changes  are 
probably  dependent  upon  occlusion  of  the  minute,  often 
tortuous,  ducts,  and  are  doubtless  intensified  by  invasion 
of  bacteria  from  the  intestine  or  stomach.  The  ducts 
are  frequently  dilated  and  in  one  instance  (Specimen  IV) 

"Warthin:    Phys.   and   Surg.,  1904,  xxvi,  337. 
"Letulle:     Compt.   rend.    Soe.   de  biol.,   1900,   lii,   233. 


38  DISEASE  OF  THE  PANCREAS 

some  of  them  contain  polynuclear  leucocytes.  In  two 
nodules  situated  in  the  jejunum,  chronic  inflammation  had 
reached  an  advanced  stage  and  one  nodule  (Specimen 
IX)  consisted  in  great  part  of  fibrous  tissue  and  dilated 
ducts  surrounded  by  hypertrophied  mucous  glands,  while 
in  the  other  nodule  (Specimen  X)  the  pancreatic  acini 
had  undergone  complete  destruction.  In  these  cases  the 
nodules  resembled  small  adenomata,  and  similar  nodules 
in  gastric  or  intestinal  wall  have  been  erroneously  de 
scribed  as  new  growths. 

Eloesser  ^^  and  Branham^^  suggest  that  malignant 
growth  may  have  its  origin  in  misplaced  pancreatic 
tissue.  The  tumor  described  by  Eloesser  as  scirrhous 
carcinoma  of  the  papilla  of  Vater  was  believed  to  have 
had  its  origin  in  aberrant  pancreatic  tissue;  description 
of  the  growth  furnishes  no  evidence  of  such  origin  and 
fails  to  establish  any  relationship  to  an  aberrant  pan- 
creatic nodule  which  was  found  in  the  wall  of  the  stomach. 
In  the  case  of  Branham  a  mass  two  inches  long  and  one 
inch  across  occupied  the  anterior  and  inferior  wall  of 
the'  pylorus.  Microscopical  examination  made  by  Prof. 
Welch  showed  the  presence  of  pancreatic  acini;  from 
these  acini  had  arisen  branching  alveoli  which  varied  in 
size  and  shape  and  invaded  both  the  muscular  and  mucous 
coats  of  the  stomach.  The  tumor  had  the  characters  of 
a  malignant  adenoma. 

Aberrant  Pancreatic  Tissue  in  the  Duodenal  Papilla 
{Santorini)  and  in  the  Biliary  Papilla. — Helly^^  has 
directed  attention  to  certain  microscopic  peculiarities  of 

"Eloesser:  Mitt.  a.  d.  Grenz.  d.  Med.  u.  Chir.,  1907,  xviii,  195. 
"  Branham :  Mai-yland  Med.  Jour.,  1908,  144. 
"Helly:  Arch.  f.  mik.  Anat.,  1900,  Ivi,  291. 


ANOMALIES  OF  THE  PANCREAS  39 

the  lesser  duodenal  papilla.  In  addition  to  the  duct  the 
papilla  contains  mucous  glands,  but  of  greater  interest  is 
the  occurrence  (in  24  of  50  instances)  of  pancreatic 
tissue  which  is  either  wholly  separated  from  the  body  of 
the  gland  by  the  muscular  coat  of  the  intestine  or  is  dis- 
tributed along  the  duct  as  it  penetrates  the  muscularis. 
A  nodule  of  considerable  size,  formed  by  numerous 
lobules,  may  be  situated  near  the  orifice  of  the  duct  imme- 
diately below  the  mucosa.  The  duct  of  this  pancreatic 
tissue  does  not  always  enter  the  duct  of  Santorini,  but 
may  open  independently  upon  the  overlying  mucosa; 
the  nodule  then  constitutes  a  true  accessory  pancreas. 

I  have  been  able  to  confirm  the  observations  of  Helly ; 
in  thirty-five  specimens  in  which  the  lesser  papilla  has 
been  examined  to  determine  the  patency  of  the  duct  of 
Santorini,  pancreatic  tissue  is  absent  in  only  six  instances. 
A  compact  mass  of  normal  pancreatic  tissue,  often  0.5 
centimetre  across,  may  lie  above  the  duct  of  Santorini 
as  it  passes  obliquely  through  the  submucosa  of  the 
duodenum.  Occasionally  individual  lobules  are  sepa- 
rated by  coarse  bands  of  connective  tissue,  and  not  in- 
frequently the  isolated  glandular  tissue  has  undergone 
such  advanced  chronic  interstitial  inflammation  that 
atrophied  acini  are  recognizable  only  by  comparison  with 
adjacent  less  changed  parenchyma.  The  duct  which 
drains  this  tissue  within  the  papilla  usually  enters  the 
duct  of  Santorini,  but  in  one  of  my  cases  serial  sections 
have  shown  that  it  opens  independently  into  the  duode- 
num. In  one  instance  the  duct  of  Santorini  does  not 
penetrate  the  duodenal  mucosa,  but  joins  the  duct  of 
Wirsung;  one  of  its  twigs  has  its  origin  in  small  branches 
draining  pancreatic  lobules  within  the  papilla. 


40  DISEASE  OF  THE  PANCREAS 

To  explain  the  occurrence  of  an  accessory  pancreas 
within  the  papilla  Helly  suggests  that  the  isolated  bit 
of  glandular  tissue  may  arise  as  a  bud  nipped  off  from 
the  dorsal  embryonic  rudiment  of  the  pancreas ;  its  ducts 
later  form  an  independent  communication  with  the 
duodenum.  In  a  later  publication  Helly  ^^  has  described 
the  development  of  the  lesser  pancreatic  papilla.  The 
outgrowth  of  duodenal  epithelium  which  represents  the 
dorsal  rudiment  of  the  pancreas  penetrates  the  meso- 
blastic  part  of  the  intestinal  wall,  and  at  a  very  early 
period  one  or  more  lateral  buds  sprout  into  the  intes- 
tinal wall  between  the  mucosa  and  the  muscularis.  From 
such  a  lateral  projection  are  formed  lobules  of  pancreatic 
acini  lying  below  the  mucosa. 

Helly  has  never  found  pancreatic  tissue  surrounding 
the  duct  of  Wirsung  as  it  penetrates  the  duodenum. 
Pilliet  ^^  has  described  glandular  tissue  in  the  bile  papilla 
but  his  description  indicates  that  he  observed  mucous 
glands,  but  no  pancreatic  tissue,  about  the  ducts.  Never- 
theless, in  one  of  my  specimens,  in  which  the  bile  papilla 
was  very  large,  microscopic  examination  demonstrated 
the  presence  of  pancreatic  lobules  surrounding  the  duct 
of  Wirsimg  as  it  approached  the  bile  duct  (see  accessory 
pancreas,  Specimen  IX,  p.  34). 

Origin  of  the  Accessory  Pancreas. — The  origin  of  the 
accessory  bodies  under  consideration  has  excited  much 
interest.  Zenker  has  thought  that  they  are  referable  to 
an  abnormal  pancreatic  rudiment  or  ''anlage"  which  iS 
formed  in  close  proximity  to  the  primitive  pancreatic 

"Helly:  Arch.  f.  mik.  Anat.,  1901,  Ivii,  271. 

"Pilliet:     Compt.   rend.    Soc.   de   biol.,   1894,    xlvi,   549. 


ANOMALIES  OF  THE  PANCREAS  41 

outgrowth  of  the  intestinal  tract  and  is  subsequently 
separated  from  it  by  the  longitudinal  growth  of  the  in- 
testinal wall.  Arising  before  the  stomach  is  distinct 
from  the  duodenum,  the  accessory  body,  carried  upward, 
would  finally  occupy  the  gastric  wall,  while  if  situated 
below  the  pancreas  it  would  be  transported  in  the  direc- 
tion of  the  ileocaecal  valve. 

To  exi3lain  the  occurrence  of  these  bodies,  Glinski 
directs  attention  to  the  development  of  the  pancreas  from 
more  than  one  rudimentary  outgrowth  of  the  intestine. 
Most  recent  observers,  mentioned  before,  have  described 
one  dorsal  and  two  ventral  diverticula,  but  in  order  to 
explain  the  existence  of  two  accessory  glands,  as  in  the 
case  described  by  Zenker,  it  would  be  necessary  to  assume 
the  existence  of  four  original  ''anlage." 

The  orifice  of  the  duct  of  Santorini,  which  represents 
the  dorsal  embryonic  outgrowth,  has  been  found  in  one 
hundred  subjects  which  I  have  examined  to  be  constantly 
situated  above  (nearer  the  stomach)  the  duct  of  Wirsung, 
which  represents  the  ventral  outgrowth,  and  is  always 
in  contact  with  the  common  bile  duct.  Should  an  acces- 
sory pancreas  arise  by  persistence  of  one  of  the  two 
ventral  outgrowths,  subsequent  lengthening  of  the  intes- 
tine would  carry  it  in  only  one  direction, — namely,  to- 
ward the  jejunum;  while  should  it  arise  from  part  of  a 
double  dorsal  outgrowth,  as  Glinski  suggests,  it  would 
be  transported  upward  in  the  direction  of  the  stomach. 
The  occurrence  of  two  aberrant  glands  above  the  pan- 
creas, as  in  Specimens  V  and  VT,  would  then  be  explicable 
only  by  assuming  the  occasional  occurrence  of  a  triple 
primitive  dorsal  rudiment,  since,  at  least  in  the  cases 
which  I  have  described,  both  pancreatic  ducts  have  de- 


42  DISEASE  OF  THE  PANCREAS 

veloped  normally.  Such  multiple  anlage  have  not  been 
found  in  any  vertebrate  species. 

Helly  has  shown  that  a  small  mass  of  pancreatic 
lobules  may  occur  in  the  papilla  of  the  duct  of  Santorini 
wholly  separated  from  the  remainder  of  the  gland.  At 
an  early  period  of  development  lateral  branches  of  the 
dorsal  pancreatic  outgrowth  penetrate  the  submucosa 
or  muscularis  of  the  intestine,  ultimately  forming  lobules 
which  surround  the  duct  as  it  passes  obliquely  through 
the  intestinal  wall.  Should  the  duct  draining  such  aber- 
rant lobules  be  occluded  by  the  development  of  adjacent 
muscular  bundles  or  fibrous  tissue,  it  is  not  improbable 
that  a  new  duct  might  be  established, — for  it  has  long 
been  known  that  the  pancreatic  duct  after  section  or  liga- 
tion regenerates  and  re-establishes  its  lumen.  This  fact 
was  known  to  Claude  Bernard;  Pawlow  and  Smirnow^^ 
described  in  detail  an  experiment  upon  a  rabbit  in  which 
two  months  after  ligating  the  pancreatic  duct  a  new 
channel  entering  the  duodenum  was  found  beside  the 
ligature  and  Ssobolew,^^  among  others,  noted  similar 
regeneration  of  the  duct. 

Should  one  or  more  embryonic  buds  of  glandular 
tissue  make  their  way  into  the  wall  of  the  intestine  at  an 
early  period,  they  might  be  carried  from  the  remainder 
of  the  gland  by  the  longitudinal  growth  of  the  intestine ; 
arising  from  the  dorsal  pancreatic  outgrowth  which  is 
situated  above  the  ventral,  the  aberrant  tissue  would  be 
carried  toward  the  stomach ;  if  it  arose  from  the  ventral 
outgrowth,  toward  the  jejunum.     The  existence  of  more 

"Pawlow  and  Smimow:    Arzt,  1889,  No.  12.     Ref.  Jahresb.  u.  d. 
Fortschr.  d.  Anat.  u.  Phys.,  1890,  xix,  Phys.  Abt.,  439. 
"Ssobolew:    Virchow's   Arch.,   1902,   clxviii,   91. 


ANOMALIES  OF  THE  PANCREAS  43 

than  one  accessory  body  above  or  below  the  pancreas 
is  then  explicable  without  assuming  the  occurrence  of  an 
embryonic  condition  unknown  among  the  vertebrates. 

In  accordance  with  this  conception,  accessory  bodies 
are  formed  by  a  process  similar  to  that  which  so  fre- 
quently isolates  a  bit  of  pancreatic  substance  in  the  pa- 
pilla of  the  duct  of  Santorini.  In  the  specimens  in  which 
an  examination  was  made,  pancreatic  tissue  was  found 
in  the  lesser  or  greater  papilla  when  an  accessory  nodule 
occurred  above  or  below  the  pancreas.  In  Specimens  V 
and  VI  the  papilla  of  the  duct  of  Santorini  was  exam- 
ined microscopically  and  found  to  contain  lobules  of 
pancreatic  tissue.  In  Specimen  V,  in  which  an  aberrant 
pancreas  occurred  in  the  stomach  and  another  in  the 
duodenum  immediately  below  the  pylorus,  the  papilla 
of  the  duct  of  Santorini  contained  a  third  isolated  nodule 
of  pancreatic  tissue.  Of  greater  import  is  Specimen  IX, 
in  which  an  accessory  body  occurred  in  the  jejunum; 
here  the  bile  papilla  contained  lobules  of  pancreatic  acini 
— a  condition  never  observed  by  Helly.  If  an  accessory 
body  arises  from  the  ventral  embryonic  outgrowth  at  a 
time  when  the  distance  between  the  hepatic  duct  and  the 
umbilical  stalk  is  slight,  subsequent  growth  of  the  intes- 
tine will  locate  it  at  some  point  between  these  structures. 
Wright  has  reported  an  unique  case  in  which  a  nodule 
of  pancreatic  tissue  was  removed  from  the  neighborhood 
of  the  umbilicus  during  life. 

The  case  of  Thorel  in  which  an  aberrant  nodule  has 
occurred  in  the  mesentery  whereas  a  similar  body  has 
been  situated  in  the  jejunum  near  by,  and  the  case  of 
Warthin  in  which  aberrant  pancreatic  tissue  has  been 
found  in  the  omentum  near  the  greater  curvature  of  the 


44  DISEASE  OF  THE  PANCREAS 

stomach,  are  explained  by  longitudinal  transportation  in 
the  gastro-intestinal  wall  and  subsequent  growth  into  the 
adjacent  fatty  tissue.  To  explain  such  anomalies  it  is 
unnecessary  with  Endres  '^  to  assume  that  rudimentary 
pancreatic  tissue  is  ensnared  and  transported  in  the  wall 
of  a  developing  blood-vessel. 

DIVERTICULA  CAUSED  BY  ANOMALIES  OF  THE  PANCREAS. 

Diverticula  of  the  Stomach  and  Intestine  with  Acces- 
sory Pancreas, — Among  recorded  instances  of  accessory 
pancreas  are  several  associated  with  diverticula  of  the 
intestine  occurring  in  the  jejunum  or  ileum  and  one  with 
diverticulum  of  the  stomach.  In  a  case  of  Zenker  a 
nodule  of  pancreatic  tissue  was  situated  at  the  summit 
of  a  diverticulum  of  the  ileum  5.5  centimetres  in  length 
and  54  centimetres  from  the  ileocaecal  valve.  Neu- 
mann ^^  found  in  a  child  ten  months  of  age  a  diverticulum 
situated  60  cm.  from  the  valve  and  capped  by  an  acces- 
sory pancreas  the  size  of  a  pea.  In  a  case  of  Nauwerk  ^^ 
a  small  mass  of  pancreatic  tissue  was  located  at  the 
apex  of  a  funnel-shaped  intestinal  diverticulum  2.3 
metres  from  the  valve.  Bize  ^^  cites  from  the  literature 
of  the  subject  cases  of  Schmauser  (two),  Heller  (two), 
Schirmer  and  Brunner,^^  ^nd  describes  two  cases  which 
he  has  observed.  Such  diverticula  have  usually  been 
found  in  eliildren  from  less  than  one  (Neumann)  to  four- 
teen (Hansemann  ^^)  years  old. 

"Endres:  Arch.  f.  mik.  Anat.,  1892,  xl,  435. 
'"Neumann:  Arch.    d.   Heilkunde,   1870,   xi,   200. 
''"  Nauwerk  :  Ziegler's  Beitrage,  1893,  xii,  29. 
'"  Bize :  Rev.  d'orthop.,  1904,  v,  149. 
''  Brunner :  Beit.  z.  klin.  Chir.,  1899,  xxv,  344. 
^  Ilanseiiiann  :  Virchow's  Arch.,  1896,  cxliv,  400. 


ANOMALIES  OF  THE  PANCREAS  45 

Weichselbaum  ^^  found  an  aberrant  pancreas  at  the 
tip  of  a  diverticulum  in  the  wall  of  the  stomach. 

Zenker  and  Albrecht^^  thought  that  the  diverticula 
which  they  described  were  the  remains  of  the  vitelline 
duct  and  represented  so-called  Meckel's  diverticula. 
Since  the  pancreas  begins  its  development  at  a  period 
when  the  vitelline  duct  is  already  formed,  Neumann  did 
not  think  the  accessory  pancreatic  nodule  could  occupy 
the  summit  of  a  diverticulum  formed  from  that  structure. 
Nauwerk  confirmed  this  view,  for  in  his  case  a  true 
Meckel 's  diverticulum  occupied  the  wall  of  the  ileum  be- 
tween the  ileocsecal  valve  and  a  diverticulum  upon  which 
was  situated  an  aberrant  pancreas. 

The  formation  of  a  diverticulum  accompanying  the 
accessory  gland  is  thought  by  Neumann,  Nauwerk,  and 
Hansemann  to  be  the  result  of  traction  exerted  by  the 
aberrant  nodule.  Accessory  pancreatic  tissue,  it  has 
been  shown  above,  is  usually  situated  in  the  muscular 
layer  of  the  intestine,  separating  and  distorting  the 
muscular  bundles  and  at  times  (Specimen  VI)  causing 
a  defect  in  the  muscular  coat.  Pressure  within  the  in- 
testine during  peristalsis  doubtless  causes  a  hernial 
protrusion  of  the  mucosa  and  submucosa  through  the 
weakened  muscularis.  It  is  improbable  that  the  small 
nodule  of  tissue  exerts  appreciable  traction  upon  the 
intestinal  wall. 

Diverticula  of  the  intestine  caused  by  aberrant  pan- 
creatic nodules  have  some  clinical  significance.  In  cases 
of  Brunner  and  of  Bize  there  were  symptoms  of  intes- 

"  Weiehselbaiim.     Quoted  by  Warthin. 

^  Albreeht :  Sitzungsb.  d.  Gesellsch.  f .  Morph.  u.  Physiol,  in  Miin- 
schen,  1907,  Hft.  i. 


46  DISEASE  OF  THE  PANCREAS 

tinal  obstruction, — namely,  abdominal  pain  and  disten- 
tion, constipation  and  fecal  vomiting, — occurring  in  chil- 
dren four  and  a  half  and  six  years  of  age  respectively. 
Operation  in  each  case  disclosed  invagination  of  the 
small  intestine  through  the  ileocascal  valve  into  the  large 
intestine,  and  at  the  extremity  of  the  invaginated  intes- 
tine was  found  a  diverticulum  inverted  into  the  lumen 
of  the  intestine  and  bearing  at  its  end  a  small  mass  of 
pancreatic  tissue.  In  the  case  of  Bize  the  invagination 
was  reduced  and  a  loop  of  intestine  carrying  a  diverticu- 
lum 4  cm.  in  length  was  resected,  but  death  occurred  two 
days  later.  The  diverticulum  was  the  seat  of  acute 
inflammation. 

In  a  boy  twelve  years  of  age  operation  was  performed 
by  Clogg  2^  for  the  relief  of  symptoms  of  intestinal  ob- 
struction; there  was  a  rounded  resonant  swelling  in  the 
right  iliac  and  hypogastric  regions  of  the  abdomen. 
About  one  foot  of  small  intestine  was  snared  under  a 
band  and,  twisted  upon  its  mesenteric  axis,  appeared  gan- 
grenous. Eesection  of  the  intestine  together  with  ex- 
cision of  the  constricting  band  was  followed  by  recovery. 
The  band  proved  to  be  an  intestinal  diverticulum  with  a 
flattened  mass  of  pancreatic  tissue  at  the  apex.  Thom- 
son ^^  found  at  operation,  undertaken  after  sudden  onset 
of  abdominal  pain  and  fever  (103°  F.)  in  a  man  thirty 
years  old,  a  diverticulum  surmourited  by  an  aberrant 
pancreas  situated  eighteen  inches  from  the  ileocsBcal 
valve.    Recovery  followed  removal  of  the  diverticulimo. 

Diverticula  of  the  Duodenum  in  Contact  with  the  Pan- 

"  Clogg:  Lancet,  1908,  i,  639. 
"  Thomson :  Lancet,  1908,  i,  860. 


ANOMALIES  OF  THE  PANCREAS  47 

creas. — Diverticula  of  the  duodenum  in  contact  with  the 
head  of  the  pancreas  not  infrequently  occur  and  doubtless 
like  those  just  described  owe  their  origin  to  weakening 
of  the  intestinal  wall  by  presence  of  pancreatic  tissue. 
Several  older  writers  quoted  by  Eoth  ^  have  observed 
such  diverticula,  and  Eoth  has  described  five  instances 
in  which  the  mucosa  of  the  duodenum  passing  through 
the  muscular  coat  formed  a  hernial  protrusion  into  the 
head  of  the  pancreas.  In  two  instances  two  such  diver- 
ticula were  present,  one  opening  beside  the  bile  papilla 
and  the  other  nearer  the  stomach;  in  one  instance  the 
opening  of  the  pouch  which  was  nearer  the  stomach  was 
in  contact  with  the  papilla  of  the  duct  of  Santorini  while 
in  the  other  instance  its  relation  to  the  duct  was  not 
noted.  In  a  third  specimen  a  single  diverticulum  was 
situated  beside  the  smaller  duodenal  papilla  and  in  a 
fourth  a  diverticulum  was  located  three  centimetres 
above  the  bile  duct,  but  its  relation  to  the  smaller  papilla 
was  not  observed.  For  a  fifth  example  the  location  of 
the  diverticulum  was  not  definitely  recorded. 

The  following  case  illustrates  the  relationship  of 
diverticula  of  the  duodenum  to  the  pancreatic  and  com- 
mon bile  ducts : 

Specimen  XI. — Diverticula  of  the  duodenum  heside  the  hile  papilla 
and  the  papilla  of  the  duct  of  Santorini.  In  the  mucous  membrane 
of  the  duodenum,  immediately  above  the  bile  papilla,  is  the  oval  orifice 
of  a  diverticulum,  which  is  1.5  cm.  in  length.  After  partial  dissection 
of  the  pancreas  from  the  duodenum,  the  mucosa  is  found  to  form 
a  hernial  protrusion  through  the  muscularis.  This  diverticulum  pene- 
trates the  muscular  coat  beside  the  conunon  bile  duct  as  the  latter  passes 

"  Roth :  Virchow's  Arch.,  1872,  Ivi,  197. 


48  DISEASE  OF  THE  PANCREAS 

obliquely  through  the  wall  of  the  intestine  and  is  continued  upward 
and  backward  in  the  direction  of  the  duct.  Immediately  above  the 
papilla  of  the  duet  of  Santorini  is  a  second  somewhat  smaller  diver- 
ticulum, 1.3  cm.  in  length,  provided  with  an  oval  orifice.  It  passes  into 
the  substance  of  the  pancreas  above  the  duct,  and  consists  of  mucosa 
and  submucosa,  in  contact  with  which  are  lobules  of  pancreatic  tissue. 

One  of  these  diverticula  lies  beside  the  common  bile 
duct  as  it  penetrates  obliquely  the  duodenal  wall,  while 
the  second  is  in  contact  with  the  duct  of  Santorini. 
Klebs,-^  Hansemann,"*^  Fischer,^^  and  others  have  shown 
that  those  diverticula  of  the  mucosa,  which  are  not  un- 
common near  the  mesenteric  attachment  of  the  small  in- 
testine, occur  at  points  where  blood-vessels  penetrate, 
and  consequently  weaken  the  muscular  coats.  Roth,  re- 
viewing the  cases  which  he  has  described,  directs  atten- 
tion to  the  relative  frequency  with  which  diverticula  of 
the  duodenum  occur  in  contact  with  the  pancreas,  and 
quotes  the  opinion  of  Fleischmann  that  the  entrance  of 
the  biliary  and  pancreatic  ducts  are  points  of  predilec- 
tion, because  here  the  muscular  bundles  separate  to  allow 
the  passage  of  the  ducts.  Pressure  within  the  intestine 
produces  a  protrusion  of  the  mucosa  through  the  muscu- 
laris.  Such  diverticula  are  analogous  to  those  which 
accompany  accessory  pancreas,  for  doubtless  an  addi- 
tional factor  in  their  production  is  the  previously  de- 
scribed occurrence  of  lobules  of  pancreatic  tissue  sepa- 
rating and  distorting  the  muscular  bundles  about  the 
ducts.     Bassett  ^^  found  a  duodenal  diverticulum  beside 

"Klebs:    Die  allgemeine  Pathologic,  Theil  ii,  p.  100,  Jena,  1889. 

'"  Hansemann  :    Loc.  cit.    (p.  44.) 

"Fischer:  Jour,  of  Exper.  Med.,  1901,  v,  3.3.3. 

"  Bassett :  Trans,  of  the  Chicago  Path.  Soc,  1907,  vii,  83. 


ANOMALIES  OF  THE  PANCREAS  49 

the  termination  of  the  common  bile  duct,  and  isolated 
pancreatic  tissue  was  embedded  in  the  muscular  coats  of 
the  duodenum  above  the  pouch. 

The  occurrence  of  inflammatory  changes  in  a  duo- 
denal diverticulum  is  illustrated  by  a  second  case  de- 
scribed by  Bassett.  The  mucosa  of  a  diverticulum 
projecting  from  the  duodenum  into  the  head  of  the  pan- 
creas was  injected  and  inflamed  and  the  pouch  contained 
bloody  mucus.  What  appeared  to  be  the  duct  of  San- 
torini  ended  at  the  margin  of  the  diverticulum  and  passed 
through  a  focus  of  hemorrhagic  necrosis  with  fat  necrosis 
in  the  head  of  the  pancreas. 


CHAPTER  III. 

HISTOLOGY  OF  THE  PANCREAS. 

Before  considering  the  pathological  histology  of 
chronic  interstitial  pancreatitis  and  the  alterations  of 
the  gland  associated  with  diabetes,  certain  histological 
peculiarities  of  the  gland  will  be  described.  The  pan- 
creas is  much  more  complex  in  structure  than  the  other 
glandular  organs  which  it  closely  resembles.  Langer- 
hans/  in  an  inaugural  dissertation  published  in  1869,  has 
given  the  first  careful  description  of  its  histology,  and 
has  shown  that  the  organ  has  not  the  relatively  simple 
structure  of  the  salivary  glands. 

Langerhans  has  studied  the  pancreas  of  rabbits,  which 
in  its  essential  features  does  not  differ  from  that  of 
other  mammals.  The  smallest  ducts  end  in  the  acini, 
composed  of  high  columnar  characteristically  glandular 
cells,  containing  next  the  lumen  numerous  zymogen 
granules.  Within  almost  every  acinus,  in  contact  with 
the  secreting  cells,  Langerhans  has  found  one,  two,  or 
more  cells  of  a  different  nature  and  to  these  he  has  given 
the  name  centro-acinar  cells.  They  closely  resemble 
the  flat  spindle-shaped  cells  lining  the  very  small  ducts 
and  he  has  thought  that  the  epithelium  of  the  duct  is 
continued  over  the  secreting  cells  into  the  lumen  of  the 
acinus,  but  he  admits  that  he  is  unable  to  determine 
with  exactness  the  method  by  which  the  duct  ends. 


*  Langerhans:   Beitrage  zur  mikroskopischen  Anatomie  der  Baueh- 
speicheldriise.     Inaug.  Diss.,  Berlin,  1869. 

50 


HISTOLOGY  OF  THE  PANCREAS  51 

Distributed  at  intervals  in  the  parenchyma  are  groups 
of  cells  differing  markedly  from  those  of  the  ordinary 
glandular  type.  Such  groups  are  usually  round  and  in 
tissue  treated  two  or  three  days  with  Miiller's  fluid 
appear  with  low  magnification  as  intensely  yellow  specks. 
With  high  magnification  it  is  found  that  they  are  com- 
posed of  small  irregularly  polygonal  cells  with  a  round 
nucleus  and  refractive  homogeneous  cell  body.  Of  the 
nature  of  these  cell  groups  Langerhans  has  declared  him- 
self entirely  ignorant. 

In  injected  specimens  Kiihne  and  Lea^  have  found 
scattered  throughout  the  organ  glomerular  structures 
composed  of  dilated  and  tortuous  capillaries  and  have 
shown  that  they  represent  the  vascular  supply  for  the  cell 
groups  which  Langerhans  has  described.  The  interacinar 
islands  are  penetrated  by  numerous  wide  tortuous  capil- 
laries forming  irregular  anastomosing  channels  between 
the  columns  of  cells  which  form  these  structures.  Ma- 
terial injected  into  the  duct  of  the  gland  does  not  pene- 
trate the  islands  of  Langerhans,  and  Dogiel  ^  was  able  to 
demonstrate  by  Grolgi's  stain  the  absence  of  ducts  within 

them. 

PANCREATIC  LOBULE. 

In  the  human  pancreas  groups  of  acini  about  terminal 
ducts  are  not  sharply  defined  by  connective  tissue,  so 
that  individual  lobules,  as  in  the  human  liver,  are  indis- 
tinctly marked  off  and  in  places  apparently  fuse  with  one 
another.  In  the  pancreas  of  the  cat  the  lobules,  like 
those  in  the  liver  of  the  pig,  are  much  more  sharply 

*  Kiihne  and  Lea:  Untersuch.  a.  d.  phys.  Instit.  d.  Univ.  Heidel- 
berg, 1882,  ii,  488. 

'Dogiel:    Arch.  f.  Anat.  u.  Physiol.,  Anat.  Abt.,  1893,  117. 


52  DISEASE  OF  THE  PANCREAS 

outlined  by  interstitial  tissue.  The  parenchyma  is 
divided  by  septa  of  fibrous  tissue  into  small  polygonal 
areas  varying  in  size  and  shape.  When  injected  with 
Berlin  blue  a  small  ramification  of  the  duct  is  found  to 
penetrate  the  isolated  group  of  acini.  These  smallest 
subdivisions  of  the  parenchyma,  which  may  be  desig- 
nated primary  lobules,  often  appear  completely  isolated 
by  fibrous  tissue  from  those  near  by;  but  when  one  of 
them  is  traced  through  a  series  of  sections,  demarcation 
being  incomplete,  its  parenchyma  may  be  found  con- 
tinuous in  places  with  that  of  adjacent  lobules.  That 
such  polygonal  subdivisions  are  actually  independent  of 
one  another  and  represent  units  of  structure  is  readily 
demonstrated  by  causing  an  inflammatory  increase  of  the 
interstitial  tissue.  If  the  pancreas  of  a  cat  is  examined 
two  or  three  weeks  after  the  ducts  have  been  ligated,  the 
gland  is  the  seat  of  a  chronic  interstitial  inflammation, 
characterized  by  an  increase  of  the  interlobular  tissue. 
The  lobules  are  completely  separated  from  one  another 
by  narrow  bands  of  firm  fibrous  tissue  and  occur  in  sec- 
tions as  rounded,  triangular,  or  polygonal  areas  of 
parenchyma. 

The  islands  of  Langerhans  in  the  normal  pancreas  of 
the  cat  occupy  a  position  near  the  centre  of  the  lobule 
and  in  the  splenic  end  of  the  gland  each  lobule  contains 
an  island.  In  a  given  section  many  lobules,  of  which 
the  limits  are  more  or  less  distinctly  outlined,  contain 
islands  situated  near  their  centre,  while  in  neighboring 
lobules  such  structures  may  not  be  discoverable.  If, 
however,  serial  sections  (Fig.  13)  are  studied  every 
lobule  is  found  to  contain  an  island.  Their  presence 
within  the  lobule  is  not  constant  in  other  parts  of  the 


HISTOLOGY  OF  THE  PANCREAS  53 

organ,  and  at  the  extremity  of  the  descending  arm  of  the 
gland  islands  of  Langerhans  are  few  in  number. 

The  framework  of  a  typical  pancreatic  lobule  is  well 
seen  in  Fig.  14,  from  a  photograph  kindly  given  me  by 
Prof.  Flint,*  of  Yale  University.     The  preparation  has 


Fig.  13. — Camera  lucida  tracing  of  the  lobule  boundaries  in  one  of  a  scries  of  sections 
from  the  splenic  end  of  a  cat's  pancreas.  The  majority  of  the  lobules  are  well  defined. 
Those  marked  d,  e,  f,  g,  and  h  are  poorly  outlined,  bwt  are  found  to  be  morefreadily  dis- 
tinguishable when  traced  through  the  series  of  sections.  The  lobules,  whichfare  lettered 
(o  to  o),  were  traced  through  the  series,  and  each  was  found  to  contain  an  island'of  I.ang- 
erhans.situated  near  its  centre.  ThCjSection  passes  through  the  island  in  lobules^a,  e,  j,[i,  and  n. 

been  made  by  digestion  according  to  the  method  which  he 
has  described.  An  island  of  Langerhans,  outlined  by  a 
framework,  of  coarser  strands  of  stroma,  is  situated  near 
the  centre  of  a  lobule.  A  somewhat  finer  network  con- 
tains in  its  meshes  the  secreting  acini. 


*  Flint:  Arch.  f.  Anat.  u.  Physiol.,  Anat.  Abt.,  1903,  61. 


54  DISEASE  OF  THE  PANCREAS 

Primary  lobules  of  the  cat's  pancreas  are  grouped 
about  the  medium-sized  ducts.  The  main  ducts  give  off 
branches  approximately  at  right  angles  to  their  course. 
Branching  one  or  more  times,  such  a  duct  forms  the 
centre  of  a  group  of  lobules,  which  is  usually  elongated 
in  form  and  tapers  to  a  point  at  or  near  the  surface  of 
the  gland.  Such  lobule-groups,  or  secondary  lobules, 
as  they  may  be  conveniently  called,  are  separated  from 
one  another  by  relatively  wide  bands  of  areolar  tissue, 
much  looser  in  texture  than  that  separating  the  individ- 
ual lobules.  The  lobule-groups  in  the  fresh  state  or  in 
tissue  macerated  a  few  days  in  Miiller's  fluid  may  be 
separated  from  one  another  by  careful  teasing.  In  the 
loose  tissue  lie  the  larger  ducts,  arteries,  veins  and 
nerves.  An  artery  and  a  vein  penetrate  each  lobule- 
group  in  company  with  the  duct  and  ramify  between  its 
lobules.  The  smallest  arteries  occasionally  penetrate  the 
lobules,  but  usually  interlobular  branches  diminishing 
in  size  give  off  capillaries  which  enter  the  lobule  and 
form  a  close  network  between  the  glandular  acini. 

In  the  human  pancreas  primary  lobules  ^'  and  groups 
of  lobules  are  not  so  regularly  arranged  as  in  the  cat, 
but  both  structures  are  definable  (Fig.  15).  The  lobules 
vary  much  in  size  (from  1  to  2.5  mm.  across)  and  are 
usually  not  clearly  separated  from  one  another.  Though 
an  island  of  Langerhans  is  often  situated  in  the  centre 
of  a  more  or  less  clearly  defined  lobule,  no  constancy  of 


•Lagnesse  (Le  pancreas,  Rev.  gen.  d'histol.,  1905,  i,  552),  desig- 
nates tliis  subdivision  "lobulin"  and  following  Renaut  (Traite  d'his- 
tologie,  Paris,  1899,  ii,  1506)  regards  the  group  of  smallest  subdivisions 
as  a  lobule.  The  dimensions  given  in  the  text  are  from  the  monograph 
of  Laguesse. 


Fig.  14. — Supporting  connective-tissue  framework  of  a  pancreatic  lobule  after  digestion  of  the 
parenchyma  by  pancreatin.     From  a  specimen  prepared  by  Professor  J.  M.  Flint. 


HISTOLOGY  OF  THE  PANCREAS 


55 


position  is  discoverable.  Groups  of  from  six  to  twenty 
lobules,  secondary  lobules,  are  separated  by  relatively 
wide  bands  of  loose  areolar  tissue  in  which  are  contained 
the  larger  ducts,  the  blood-vessels,  and  the  nerves;  the 
secondary  lobules  give  to  the  surface  of  the  gland  its 
characteristic  lobulated  appearance  and  vary  in  width 


a.Y 


Fig.  15. — Lobules  of  the  human  pancreas  grouped  to  folm  a  secondary  lobule.  (After 
Laguesse,  Rev.  g&.  d'histol.,  1904-5,  i,  552)  1,  1',  1",  1'",  1"",  lobules;  i,  islandJofiLang- 
erhans;  ca,  duct;  a.v,  artery  and  vein. 

from  two  to  six  millimetres.  Within  the  secondary 
lobule  the  arteries  and  veins,  which  are  side  by  side,  do 
not,  as  in  the  cat,  accompany  the  ducts.  It  has  been 
mentioned  in  a  previous  chapter  that  several  secondary 
lobules  are  usually  grouped  together  to  form  tertiary 
lobules,  and  these  represent  the  largest  subdivisions  seen 
upon  the  surface  of  the  organ. 


DUCTS  AND  ACINI. 

Ducts. — The  large  ducts  of  the  pancreas,  including  the 
duct  of  Wirsung  and  the  duct  of  Santorini  and  their 
largest  branches,  have  a  wall  of  connective  tissue  in 


56  DISEASE  OF  THE  PANCREAS 

which  are  both  white  and  elastic  fibres  and  are  lined  by 
a  single  layer  of  columnar  cells.  Since  granules  occur 
in  the  inner  zone  of  these  cells,  and  reactions  to  stains 
indicate  the  presence  of  mucin,  many  observers  believe 
that  they  have  a  secretion  which  they  discharge  to  mix 
with  the  secretion  of  the  alveoli.  In  the  wall  of  the  duct 
of  Wirsung  occur  small  crypts  and  ramified  gland-like 
structures  which  have  the  characters  of  mucous  glands. 
The  ducts  of  medium  size  situated  within  the  secondary 
lobules  have  little  connective  tissue  in  their  wall  and  are 
lined  by  low  cylindrical  or  cubical  cells.  The  smallest  ducts 
(intercalary  ducts)  about  which  the  acini  are  grouped  are 
formed  by  flat  cells  with  a  large  oval  nucleus.  When  the 
duct  is  cut  longitudinally  these  cells,  of  which  the  central 
part  is  distended  by  the  nucleus,  are  spindle-shaped  in 
outline. 

Acini. — The  shape  of  the  acini  differs  in  different 
animals  and  has  caused  confusion  in  classification  of  the 
gland.  With  the  rabbit  the  acini  are  tubular  and 
branched;  in  the  hen,  especially  at  the  surface  of  the 
lobules,  the  tubular  acini  anastomose.  Maziarski®  has 
shown  by  the  method  of  reconstruction  that  the  acini  of 
the  human  pancreas  are  round  or  oval,  and  occasionally 
have  a  lobed  surface  but  do  not  branch. 

The  pancreatic  cells  which  form  the  acini  have  the 
shape  of  a  truncated  pyramid  with  the  apex  directed 
toward  the  lumen  of  the  acinus.  Two  zones  are  distin- 
guishable, namely,  an  apical  zone  containing  refractive 
zymogen  granules  (described  by  Claude  Bernard  in 
1856)  and  a  basal  zone  which  is  homogeneous  save  for 


Maziarski:  Anat.  Ilefte,  1901,  Hft.  Iviii,  171. 


HISTOLOGY  OF  THE  PANCREAS  57 

the  presence  of  striations  parallel  with  the  long  axis  of 
the  cell.  In  hardened  specimens  the  zymogen  granules 
of  the  apical  zone  stain  with  certain  acid  dyes,  whereas 
the  protoplasm  of  the  basal  zone  stains  deeply  with 
hematoxylin.  The  nucleus  situated  near  the  base  of  the 
cell  is  spherical  or  occasionally  oval;  its  well-defined 
nuclear  membrane  gives  it  a  vesicular  appearance,  and  in 
the  nuclear  network  there  is  usually  a  large  nucleolus. 

Within  the  acini  in  contact  with  the  apices  of  the 
secreting  cells  are  the  centro-acinar  cells  described  by 
Langerhans;  they  are  fusiform,  often  flat,  and  may  be 
provided  with  short  projections  which  penetrate  between 
the  secreting  cells.  The  protoplasm  is  almost  homo- 
geneous and  the  nucleus  is  distinguishable  from  that  of 
the  secreting  cells  by  its  small  size,  oval  shape,  and 
greater  richness  in  chromatin.  These  cells  closely  re- 
semble the  cells  of  the  terminal  ducts  with  which  they 
appear  to  be  continuous,  as  though  the  duct  projects  into 
the  lumen  of  the  acinus.  Concerning  the  significance  of 
these  cells  little  is  known. 

When  colored  fluid  is  injected  into  the  acinus  through 
ducts  of  the  gland,  the  injected  fluid  penetrates  between 
the  secreting  cells  and  marks  out  short  channels  which 
often  have  a  terminal  enlargement.  The  claim  that  these 
intercellular  canals,  first  demonstrated  by  Langerhans, 
are  artificially  produced  by  the  injection  has  been  dis- 
proven  by  Eamon  y  Cajal  and  Sala,^  who  have  employed 
the  Golgi  method  to  stain  the  secretion  contained  in  the 
terminal  ramifications  of  the  duct. 

Changes  in  the  Acini  with  Secretion. — When  the  gland 

'  Ramon  y  Cajal  and  Sala :    Termination  de  los  nervios  y  tubes 
glandulares  del  jDancreas.     Barcelona,  1891.     Quoted  by  Laguesse. 


58  DISEASE  OF  THE  PANCREAS 

is  engaged  in  producing  its  secretion  changes  occur  in 
the  cells  of  the  acini  (Fig.  16).  Heidenhain^  has  de- 
scribed the  changes  observable  in  sections  prepared  from 
the  pancreas  of  a  dog  kept  twenty-four  hours  without 


F1G.TI6. — Pancreatic  acini  showing  variation  during  secretion.  1.  Pancreatic  acini 
of  dog;7a,  6,'c,  acinifcontaining  zjTnogenCgranules;  ce,  duct.  2.  Acini  a,  b,  c  d,  after  stim- 
ulationjofjthe^'gland  by  pilocarpin;  ca,  centro-acinar  cell;  ce,  duct. 

food.  During  the  first  six  or  ten  hours  after  a  full  meal 
the  inner  zone,  containing  granules,  decreases  until  in 
many  cells  it  occupies  only  the  tip  of  the  cell.     The  outer 


'  Heidenhain :  Arch,  f .  d.  ges.  Physiol,  1875,  x,  557. 


»o  ^ 


'%yl     @  ^' 


4^ 


Fig.  17. — Island  of   Langerlians  of  the  human  pancreas.     (Figs.  17,  18,  24   26  28,  30,  32,  and 
49  are  from  drawings  made  by  Miss  E.  S.  Carrington.) 


HISTOLOGY  OF  THE  PANCREAS  59 

zone,  which  stains  deeply  with  hsematoxylin,  increases  in 
height  but  its  increase  does  not  keep  pace  with  decrease 
of  the  apical  zone,  and  the  cell  diminishes  in  size.  Dur- 
ing a  second  stage,  lasting  from  the  tenth  to  the  twen- 
tieth hour  after  taking  of  food,  the  cell  increases  in  vol- 
ume; accumulation  of  granules  increases  the  apical  zone 
and  diminishes  the  basal  zone.  When  animals  are  fed 
at  short  intervals  part  of  the  gland  will  be  in  one  stage 
of  secretion  whereas  groups  of  acini  will  be  in  the  other 
stage.  Kiihne  and  Lea  have  followed  the  course  of  the 
foregoing  changes  in  the  pancreas  of  the  living  rabbit, 
exposed  with  proper  precautions  under  the  microscope. 
Experiments  of  Ileidenhain  have  shown  that  the 
abundance  of  granules  in  the  apical  zone  of  the  secreting 
cells  bears  a  relation  to  the  quantity  of  zymogen  which 
can  be  extracted  from  the  gland.  The  fresh  gland  does 
not  contain  active  trypsin  but  its  precursor  is  abundant 
in  the  fasting  animal,  and  gradually  diminishes  during 
the  first  six  or  ten  hours  after  a  meal ;  subsequently  there 
is  gradual  increase  of  tryptic  zymogen.  The  fat-split- 
ting and  amylolytic  enzymes  obtainable  from  the  fresh 
gland  undergo  similar  changes  after  a  meal,  but  the  rela- 
tion of  these  enzymes  to  the  granules  of  the  secreting  cells 
has  been  questioned. 

ISLANDS  OF  LANGERHANS. 

The  structures  which  are  usually  designated  islands 
of  Langerhans  (Fig.  17)  have  been  described  under  a 
variety  of  names.  Renaut,^  regarding  them  as  analogous 
to  lymph  follicles,  has  named  them  ' '  points  f olliculaires. ' ' 

*Renaut:    Compt.  rend.  d.  I'Acad.  d.  sciences,  1879,  Ixxxix,  247. 


60  DISEASE  OF  THE  PANCREAS 

Podwyssotski^o  has  called  tliem  pseudo-follicles.  They 
have  been  designated  secondary  cell-groups,  interalve- 
olar  cell  islets  and  interacinar  islands. 

Numerous  investigations  have  demonstrated  their 
occurrence  in  a  great  variety  of  vertebrate  species,  in- 
cluding numerous  mammals,  birds,  amphibia,  reptiles, 
and  fish.  Giannelli  and  Giacomini  ^^  state  that  in  certain 
reptiles  the  columns  of  cells  forming  the  islands  of  Lan- 
gerhans  have  a  tubular  structure,  being  composed  of 
moderately  high  cylindrical  cells  which,  though  they 
differ  in  appearance  from  the  ordinary  secreting  cells 
of  the  acini,  are  arranged  about  a  narrow  lumen.  At 
the  periphery  of  the  island,  these  tubular  columns  are 
continuous  with  the  secreting  acini.  In  certain  fish, 
Diamare  ^^  found  near  the  spleen,  the  hepatic  artery, 
and  in  other  situations,  isolated  structures  resembling 
islands  of  Langerhans.  Since  structures  having  the 
characters  of  islands  of  Langerhans  have  been  found 
in  a  constantly  increasing  number  of  diverse  species, 
there  can  be  little  doubt  that  they  are  present  in  all 
vertebrates. 

Various  opinions  have  been  held  concerning  the  na- 
ture of  the  interacinar  cell-groups,  and  a  number  of 
observers,  denying  the  epithelial  character  of  the  cells 
which  compose  them,  have  emphasized  a  supposed  resem- 
blance to  lymphoid  tissue.     Renaut  has  described  the 

"  Podwyssotski :  Arch.  i".  inik.  Anat.,  18S2,  xxi,  7G5. 

"  Giannelli  and  Giacotnini :  Accad.  di  Fisiocrit.,  Siena,  1896. 
Quoted  Vjy  Oppel,  Lclii-buch  der  vei-o^leichenden  raikroskopisehen 
Anatomic  der  Wirboltiere,  iii,  Jena,  11)00. 

'^Diamare:  Internal.  Monatsselii-.  f.  Anat.  u.  Pliysiol.,  1899,  xvi, 
155. 


HISTOLOGY  OF  THE  PANCREAS  61 

pancreas  as  a  lymplioglandnlar  organ  composed,  he  has 
thought,  of  glandular  structures  and  lymphoid  tissue  in 
intimate  relation.  He  has  described  the  cell-groups  as 
*' points  f olliculaires "  in  which  cells  of  a  glandular  type 
are  situated  in  the  meshes  of  a  reticular  tissue.  Kiihne 
and  Lea  and  Dieckhoff  ^^  have  thought  that  they  are  prob- 
ably small  lymph  follicles.  Schlesinger  ^*  (1898)  has 
regarded  them  as  a  variety  of  lymph  follicle  of  which  the 
cells  differ  from  those  of  ordinary  lymphoid  tissue. 
Podwyssodski  has  called  them  pseudo-follicles,  because 
they  resemble  lymph  follicles  though  their  cells  have 
nothing  in  common  with  lymphoid  cells.  The  conception 
of  Von  Hansemann  ^^  is  unique ;  the  islands  of  Langer- 
hans  are  formed,  he  believes,  by  cells  of  the  stroma.  At 
a  late  period  of  embryonic  life  capillary  blood-vessels,  he 
thinks,  assume  a  glomerular  form  and  cells  of  the  adja- 
cent stroma  increase  in  size  and  arrange  themselves  about 
the  glomerular  vessels. 

Eenaut  ^^  in  a  treatise  on  histology  abandoning  his 
former  view  describes  the  common  origin  of  the  inter- 
acinar  cell-groups  and  the  secreting  acini.  The  greater 
number  of  observers  have  held  the  same  opinion,  and 
studies  of  the  histogenesis  of  the  gland  have  conclusively 
demonstrated  its  accuracy. 

Size. — The  outline  of  the  island  of  Langerhans  in  the 
human  pancreas  is  usually  round  or  oval  and  is  not  infre- 

"  DieckhofE :  Beitrage  zur  pathologischen  Anatomie  des  Pankreas. 
Festschrift  f.  Thierfelder,  Leipzig',  1895. 

"  Schlesinger :  Virchow's  Ai-ch.,  1898,  cliv,  501. 

"*  Von  Hansemann  :  Verhandl.  der  Deutsehen  path.  Gresellsch.,  1902, 
iv,   187. 

"  Renaut :  Traite  de  histologie  practique,  Paris,  1899,  ii,  1506. 


62 


DISEASE  OF  THE  PANCREAS 


quently  accentuated  by  a  delicate  circle  of  connective 
tissue.  In  other  instances  the  outline  is  less  sharply 
defined  and  the  body  accommodates  its  shape  to  that  of 
the  neighboring  acini.  These  interacinar  structures  vary 
greatly  in  size,  the  greater  number  measuring  from  75 
to  175  microns  in  diameter  (Heiberg  ^^) ;  very  large 
islands  more  than  0.5  millimetre  in  diameter  have  been 
found.  Dewitt  ^^  has  estimated  that  the  amount  of  tissue 
forming  islands  of  Langerhans  in  three  normal  human 
glands  has  been  respectively  1/25,  1/50  and  4/500  of  the 
volume  of  the  organ.  Heiberg  estimated  the  weight  of 
islands  of  Langerhans  in  a  human  pancreas  which  he 
examined  as  2.6  grammes. 

Number. — In  the  human  pancreas  I  have  found  islands 
of  Langerhans  more  numerous  in  the  splenic  end  or  tail 
than  elsewhere.^*'  The  following  table  gives  the  number 
found  in  0.5  square  centimetre  of  section  about  ten 
microns  thick  taken  from  the  head,  body  and  tail  of  ten 
normal  organs: 


Number. 

Head. 

Body. 

Tail. 

1 

11 

30 

4 

4 

27 

25 

18 

6 

44 

14 

13 
25 
4 
10 
18 
27 
18 
10 
32 
23 

30 

2 

42 

3 

19 

4 

13 

5                

59 

6 

26 

7 

29 

8 

29 

9 

61 

10 

32 

Mean 

18.3 

18.0 

34.0 

Heiberg:    Anat.  Anz.,  1906,  xxLx,  49. 
Dewitt :  Jour,  of  Exper.  Med.,  1906,  viii,  193. 
Opie:  Johns  Hopkins  Bulletin,  1900,  xi,  205. 


HISTOLOGY  OF  THE  PANCREAS  68 

The  table  shows  that  islands  of  Langerhans  are  more 
abundant  in  the  tail  or  splenic  end  than  in  the  head  or  in 
the  body,  where  they  are  present  in  approximately  equal 
number.  They  are  almost  twice  as  numerous  in  sections 
from  the  tail  as  in  those  from  other  parts ;  but  since  the 
number  in  only  one  plane  is  recorded,  in  order  to  obtain 
their  actual  relative  abundance  it  is  necessary  to  square 
these  figures.  They  are  then  found  to  be  slightly  less 
than  three  and  a  half  times  as  numerous  in  the  tail  as 
elsewhere. 

Tables  published  by  Sauerbeck ^^  (six  individuals) 
and  by  Heiberg  (seventeen  individuals)  show  that  islands 
of  Langerhans,  save  in  a  small  proportion  of  individuals, 
are  much  more  abundant  in  the  tail  than  in  the  head  or  in 
the  body  of  the  gland.  Averages  calculated  from  the 
number  of  islands  of  Langerhans  found  by  Heiberg  in 
0.5  square  centimetre  of  tissue  are  as  follows:  Head, 
69.5;  body,  94.3;  tail,  143.8.  These  figures  differ  but 
little  from  those  of  Laguesse  ^^  and  Sauerbeck;  they  con- 
firm the  observation  that  islands  of  Langerhans  are  most 
numerous  in  the  splenic  end  of  the  gland. 

The  islands  of  Langerhans  were  found  more  numer- 
ous, as  Kasahara  ^^  pointed  out,  in  the  pancreatic  tis- 
sue of  the  foetus  and  of  very  young  children  than  in  that 
of  the  adult.  Should  we  assume  that  they  are  formed 
during  embryonic  development  and  persist  thereafter, 
this  fact  is  readily  explicable.  The  organ  being  much 
smaller  in  the  foetus  and  in  a  young  child,  the  same  num- 
ber  of  islands,   though  themselves   smaller,   are  more 

""  Sauerbeck :    Virchow's  Areli.,  1904,  clxsvii,  Suppl.,  1, 
"^ Laguesse:    Compt.  rend.  Soe.  de  bioL,  1905,  i,  504. 
° Kasahara:  Virchow's  Arch.,  1896,  exliii,  111. 


64  DISEASE  OF  THE  PANCREAS 

closely  together  and  therefore  appear  to  be  more  numer- 
ous in  sections. 

Cells. — The  cells  which  compose  the  interacinar 
islands  in  the  adult  human  pancreas  are  polygonal  in 
shape  and  smaller  than  the  cells  of  the  acini.  They  have 
a  large,  round,  occasionally  oval,  vesicular  nucleus  with 
several  small  nucleoli  and  usually  a  well-defined  cell-body. 
The  basal  zone  of  the  secreting  cell,  it  is  well  known, 
stains  deeply  with  nuclear  dyes,  for  example,  hsematoxy- 
lin  or  methylene  blue,  while  the  apical  part  which  con- 
tains zymogen  granules  remains  unstained.  The  cells 
of  the  island,  on  the  contrary,  are  entirely  unstained 
by  nuclear  dyes,  whereas,  with  eosin  their  protoplasm 
takes  a  homogeneous  bright  pink  color.  The  nuclei  vary 
considerably  in  size,  and  not  infrequently  one  finds  very 
large  round  vesicular  nuclei  the  diameter  of  which  is 
two  or  more  times  that  of  the  adjacent  cells.  The  cells 
form  columns  between  which  lie  anastomosing  capillaries. 
Occasionally  they  are  very  closely  packed  together  and 
nuclei  are  situated  almost  side  by  side ;  more  frequently, 
the  cells  of  the  island  are  less  numerous  and  nuclei  are 
less  closely  crowded. 

Dogiel  2^  and  later  Stangl  ^^  have  shown  that  fat  is 
normally  present  in  the  protoplasm  of  the  cells  which 
form  the  islands  of  Langerhans.  Numerous  very  fine 
droplets  of  almost  uniform  size  are  abundant  in  the 
islands  of  Langerhans,  whereas  fat  droplets  within  the 
secreting  acini,  often  much  larger,  vary  greatly  in  size, 
and  are  more  sparsely  scattered. 

^  Loc.  cit.,  p.  51. 

"Stangl:  Wiener  klin.  Wocli.,  1001,  xiv,  964. 


HISTOLOGY  OF  THE  PANCREAS  65 

The  protoplasm  of  the  insular  cells  is  not  entirely 
homogeneous  but,  as  Laguesse  ^s  and  others  have  shown, 
contains  minute  granules  which  stain  with  safranin, 
eosin,  gentian  violet  or  fuchsin.  Diamare  ^^  has  found 
in  the  island  of  Langerhans  of  the  rabbit  in  sections 
stained  by  methyl  green,  picric  acid  and  acid  fuchsin 
(Galeotti's  stain)  large  cells  brightly  colored  red,  scat- 
tered among  the  more  numerous  smaller  cells  which  are 
stained  green. 

By  careful  study  of  the  microchemistry  of  the  gran- 
ules contained  in  the  cells  of  the  islands  of  Langerhans 
Lane  ^^  has  demonstrated  the  existence  of  two  types  of 
cell:  (a)  Cells  of  large  size  occur  in  groups  near  the 
centre  of  the  island  of  Langerhans  and  contain  fine  gran- 
ules which  stain  with  neutral  gentian  violet  after  fixation 
with  alcohol  (50  to  70  per  cent.)  but  are  soluble  in  Miil- 
ler's  fluid  containing  bichloride  of  mercury;  while  (b) 
smaller  cells  are  more  numerous  and  contain  granules 
which  are  soluble  in  alcohol  but  are  fixed  by  Miiller's 
fluid  with  bichloride.  Each  type  of  granule  differs  in 
solubility  and  in  microchemical  reactions  from  the  zymo- 
gen granules  of  the  secreting  cells. 

Blood-Vessels. — The  capillaries  of  the  island  of  Lan- 
gerhans form  a  glomerulus  of  tortuous,  freely  anastomos- 
ing vessels,  much  wider  than  those  between  the  acini. 
A  single  afferent  vessel  like  that  of  the  glomerulus  of  the 
kidney  does  not  enter  this  group  of  dilated  capillaries, 
but  numerous  anastomoses  make  the  network  within  the 


"•'Laguesse:  Jour,    de   Fanat.   et   physioL,   1895,   xxi,   475;   Arch, 
d'anat.  mic,  1901,  iv,  157. 
''^Loc.  cit.,  p.  60. 
"  Lane :  American  Joui-.  of  Anat.,  1907,  vii,  409. 


66  DISEASE  OF  THE  PANCREAS 

island  of  Langerbans  continuous  with  the  interacinar 
capillaries  (Fig.  18).  Wlien  Berlin  blue  is  injected 
through  the  aorta  into  the  arteries  of  the  pancreas,  it 
not  infrequently  happens  that  in  parts  of  the  gland  which 
are  poorlj^  injected  the  vessels  of  the  interacinar  island 
are  filled  with  the  injected  mass,  whereas  the  surrounding 
capillaries  are  for  the  most  part  empty.  If,  instead  of 
soluble  Berlin  blue,  a  granular  injection  mass — for  ex- 
ample, cinnabar  or  ultramarine  blue — is  used,  the  islands 
of  Langerhans  ma.y  be  injected  while  the  interacinar 
capillaries  contain  little  of  the  injected  material.  Such 
observations  show  that  the  glomerular  network  is  in 
verj^  free  communication  with  the  smallest  arteries  and 
apparently  has  a  richer  blood  supply  than  other  parts 
of  the  lobule. 

HISTOGENESIS   OF  THE   SECRETING  ACINI  AND   OF  THE 
ISLANDS  OF  LANGERHANS. 

The  epithelial  nature  of  the  cells  composing  the 
islands  of  Langerhans  has  been  clearly  demonstrated  by 
embryological  investigation.  In  the  embryo  sheep  La- 
guesse^s  has  traced  the  histogenesis  of  the  gland  (Fig. 
19)  from  the  stage  in  which  the  organ  is  represented  by 
a  simple  diverticulum  from  the  intestinal  wall  (embryo 
4  millimetres) .  Solid  cords  of  cells  arise  from  this  diver- 
ticulum (embryos  4  to  18  millimetres)  and  at  the  end  of 
the  second  month  give  place  to  tortuous  anastomosing 
tubules  formed  by  a  single  layer  of  epithelial  cells  (em- 
bryos 18  to  50  millimetres).  Here  and  there  occur  cells 
which   stain  more  deeply  than  those  about  them,  and 


Laguesse:    Vcrhaiull.  d.  aiiat.  Gesellscli.,  1897,  45, 


Fig.  18. — Blood-vessels  of  the  pancreas  injected  in  order  to  show  the  glomerular  arrangement  of 
capillaries  in  the  islands  of  Langerhans. 


HISTOLOGY  OF  THE  PANCREAS 


67 


like  the  border  cells  of  the  stomach  are  situated  near 
the  outer  surface  of  the  tubule.  These  cells  proliferate 
to  form  solid  outgrowths  or  loops  upon  the  tubule  and 


Fig.  19. — Diagrams  showing  histogenesis  of  the  pancreas.  1.  Diverticulum  from  the 
intestinal  epitheliimi.  2.  Solid  branching  cords  of  cells.  3.  Tubules  which  branch  and 
anastomose  (an);  they  are  enlarged  at  the  extremities  and  have  formed  islands  of  Langer- 
hans  (ie).  4.  Formation  of  acini  (etc);  ca,  centroacinar  cells.  5.  Formation  of  a  lobed 
acinus.     (After  Laguesse,  Rev.  gdn.  d'histol.   1906,  ii,  18.) 

constitute  what  Laguesse  calls  primary  islands  of  Lan- 
gerhans.  At  a  later  stage  (embryos  60  to  65  millimetres) 
the  secreting  acini  are  formed  as  buds,  from  the  wall  of 


68  DISEASE  OF  THE  PANCREAS 

the  original  tubules,  and  within  them  can  be  recognized 
two  kinds  of  cells,  the  ordinary  glandular  cell  containing 
zymogen  granules  and  the  centro-acinar  cells  which  form 
a  second  more  or  less  continuous  row  superimposed  upon 
the  secreting  cells.  At  a  still  later  stage  (embryos  90 
millimetres),  Laguesse  thinks  that  groups  of  acini 
undergo  alterations  by  which  they  are  transformed 
directly  into  interacinar  islands,  designated  by  him  sec- 
ondary islands  of  Langerhans.  This  mode  of  formation 
has  received  no  confirmation  from  subsequent  embryo- 
logical  studies. 

Eenaut  has  described  the  histogenesis  of  the  pan- 
creatic lobule.  His  description  of  the  early  stages  of 
development  agrees  with  that  given  by  Laguesse.  The 
primitive  dorsal  and  ventral  outgrowths  from  the  wall 
of  the  duodenum  form  numerous  branches  which  ramify 
in  the  dorsal  mesentery  of  the  intestine.  At  first  these 
branches  are  solid,  but  soon  they  acquire  a  lumen  about 
which  the  cells  are  arranged  in  a  single  row,  and,  anas- 
tomosing between  themselves,  they  resemble  the  tubular 
columns  which  form  the  liver  of  certain  lower  verte- 
brates. At  intervals  along  their  wall  are  formed  short 
outgrowths  terminating  in  a  rosette-like  group  of  blind 
pouches.  Within  such  a  group  of  primitive  acini  at  least 
one  island  of  Langerhans  is  formed  by  differentiation 
and  multiplication  of  the  peculiar  cells,  already  described 
by  Laguesse.  The  rosette-like  group  of  acini  and  at 
least  one  island  of  Langerhans  represent  the  primary 
glandular  lobule  in  its  undeveloped  form  and  by  subse- 
quent growth  give  rise  to  the  primary  lobule  of  the  adult 
gland. 


HISTOLOGY  OF  THE  PANCREAS  69 

Studies  of  Pearce,^^  made  upon  the  human  embryo, 
have  clearly  established  the  common  origin  of  the  islands 
of  Langerhans  and  the  secreting  acini  and  the  final  inde- 
pendence of  these  structures.  Islands  of  Langerhans 
originate  from  cells  of  the  primitive  secreting  tubules. 
At  the  end  of  the  third  month  the  solid  stalk-like  strand 
of  cells  connecting  the  island  of  Langerhans  with  the 
acini  becomes  constricted  and  lengthened  and  complete 
separation  occurs.  The  rich  vascular  network  of  the 
interacinar  island  is  formed  about  the  same  time. 
Almost  identical  observations  have  been  subsequently 
made  by  Kiister.^*^ 

FUNCTION  OF  THE  ISLANDS  OF  LANGERHANS. 

Relation  between  Secreting  Acini  and  Islands  of  Lan- 
gerhans in  the  Adult  Pancreas, — An  attempt  to  investi- 
gate experimentally  the  nature  of  the  islands  of 
Langerhans  has  been  made  by  Lewaschew,^^  working 
in  Heidenhain's  laboratory.  He  studied  the  pancreas 
of  dogs  and  cats  killed  after  having  been  subjected  to 
conditions  which  cause  the  gland  to  secrete  actively. 
After  prolonged  overfeeding,  or  after  the  frequently 
repeated  administration  of  pilocarpin,  which  stimulates 
the  pancreas  as  it  does  the  salivary  glands,  he  claims 
to  have  found  structures  representing  transitions  be- 
tween the  glandular  acini  and  the  interacinar  cell-groups. 
He  has  observed  acini  containing  one  or  more  cells  of 
which  the  protoplasm  is  non-granular  and  stains  lightly, 
a  whole  acinus  or  a  number  of  acini  composed  of  such 

^  Pearee :     American    Jour,    of    Anat.,    1903,    ii,    445. 
'"Kuster:    Arch.  f.  mik.  Anat.,  1904,  Ixiv,  158. 
^Lewaschew:    Arch.  f.   mik.   Anat.,  1886,  xxvi,  452. 


70 


DISEASE  OF  THE  PANCREAS 


cells;  areas  in  which  cells  have  assumed  a  polygonal 
shape  and  are  no  longer  grouped  about  a  central  lumen, 
and  finally  cell-groups  formed  by  polygonal  cells  without 
acinar  arrangement,  representing,  he  thinks,  newly 
formed  islands  of  Langerhans.  Lewaschew  mentions 
that  he  has  found  an  unusual  number  of  islands  under 
conditions  other  than  those  of  increased  functional  activ- 
ity. They  were  very  numerous  in  a  dog  which  several 
days  before  its  death  had  suffered  with  fever. 

The  observations  of  Lewaschew  have  not  been  con- 
firmed. I  have  attempted  to  repeat  his  observations  by 
injecting  pilocarpin  muriate  into  dogs.^^  The  islands  of 
Langerhans  were  counted  in  0.5  square  centimetre  of 
sectional  area  in  specimens  (a)  from  the  splenic  extrem- 
ity of  the  pancreas,  (h)  from  the  part  in  contact  with  the 
duodenum,  and  (c)  from  the  descending  arm  which  lies 
in  the  mesentery  of  the  duodenum.  The  number  in  the 
pancreas  of  a  dog  which  had  received  repeated  injections 
of  pilocarpin  was  compared  with  that  found  in  cor- 
responding parts  of  the  pancreas  of  animals  to  which 
pilocarpin  had  not  been  given.  The  results  are  shown 
in  the  following  table: 


Injected  animal. 

a 

b 

c 

Control  Animal. 

a 

b 

c 

Dog  No.  1 

Dog  No.  2 

Dog  No.  3 

61 
55 
54 

21 
20 

72 

1 
11 

8 

Dog  No.  I 

Dog  No.  II 

Dog  No.  III.... 

59 
39 

67 

61 
53 

89 

14 

3 

12 

Average 

56.6 

37.6 

6.6 

Average 

55 

67.6 

9.6 

The  figures  show  that  no  increase  of  the  number  of 


Lnc.  at.,  p.  62. 


HISTOLOGY  OF  THE  PANCREAS  71 

islands  of  Langerhans  was  obtained  in  the  three  experi- 
ments. Transitional  stages  between  glandular  acini  and 
interacinar  islets  have  not  been  observed.  The  number 
of  islands  in  that  part  of  the  descending  arm  of  the  pan- 
creas whicb.  lies  in  the  mesentery  of  the  duodenum  (c) 
is  constantly  much  less  than  elsewhere;  the  number  in 
different  glands  and  in  different  parts  of  the  same  gland 
varies  considerably.  In  the  experiments  of  Lewaschew 
these  sources  of  error  apparently  have  not  been  given 
sufficient  weight.  The  effect  of  pilocarpin  upon  the 
islands  of  Langerhans  has  been  tested  with  negative 
results  by  Hansemann  and  by  Ssobolew. 

The  discovery  of  secretin  by  Starling  has  suggested 
a  means  by  which  the  secreting  cells  of  the  acini  may  be 
stimulated  to  exhaustion.  Dale,^^  a  pupil  of  Starling, 
has,  he  believes,  transformed  secreting  acini  into  islands 
of  Langerhans  by  injection  of  secretin  into  the  circula- 
tion repeated  during  from  six  to  twelve  hours;  the  injec- 
tions have  been  accompanied  by  bleeding  toward  the  end 
of  the  experiment.  After  continued  injection  of  secretin 
the  greater  part  of  lobules  in  the  dog  and  the  greater 
part  of  the  pancreas  in  the  toad  are  converted,  he  claims, 
into  tissue  resembling  cell-islets,  and  only  traces  of  alve- 
olar arrangement  suggest  its  former  condition.  Such 
widespread  changes  have  little  resemblance  to  the  cir- 
cumscribed islands  of  Langerhans  observed  in  normal 
and  pathological  pancreas,  and  suggest  the  possibility 
that  Dale  has  produced,  by  profound  injury  to  the  gland, 
degenerative  changes  in  the  parenchyma — perhaps  the 

'"Dale:    Philosoph.  Trans.,  1904,  cxevii,  B.  25. 


72  DISEASE  OF  THE  PANCREAS 

well-known  self -digestion  which,  as  Chiari  ^^  has  shown, 
may  have  its  onset  during  the  death  agony. 

Inanition. — Several  obsei-\'ei-s  have  claimed  that  secreting  acini 
are  transfoi-med  into  islands  of  Langerhans  under  conditions  which 
have  little  resemblance  to  those  previously  mentioned.  In  dogs,  cats, 
and  rabbits  which  have  been  starved,  the  secreting  cells,  Statkewitsch  ^^ 
claims,  lose  their  gi-anular  inner  zone  and  by  a  series  of  transitions 
assume  the  chai'acter  and  arrangement  of  the  interacinar  cell-groups. 
Vincent  and  Thompson ""  claim  to  have  observed  after  starvation  in- 
crease of  islands  of  Langerhans  in  the  dog,  pigeon,  and  frog.  The 
number  and  character  of  their  experiments  are  not  described  in  detail 
and  in  only  one  instance  have  islands  of  Langerhans  been  compared 
numerically  with  those  of  a  nonual  control  animal.  They  state  that 
changes  following  inanition  are  more  marked  than  those  following 
the  injection  of  secretin  which  produces,  they  think,  some  increase  of 
interacinar  islands. 

Jarotzky "  has  made  a  careful  study  of  the  secreting  pancreatic 
cells  in  mice  under  various  conditions  of  inanition;  from  some  of  his 
animals  food  was  withheld,  others  were  given  only  sugar,  others  only 
fat,  but  in  none  did  he  find  changes  similar  to  those  described  by 
Statkewitsch.  Ssobolew  found  no  transformation  of  acini  into  inter- 
acinar islands  with  inanition.  Dewitt  made  measurements  of  the  size 
and  number  of  interacinar  islands  in  guinea-pigs  after  withdrawal  of 
food,  and  after  continued  diet  of  meat  or  of  carbohydrates,  but  found 
no  departure  from  the  normal. 

Appearances  Believed  to  Represent  Transition  from  Acini  to 
Islands  of  Langerhans. — A  considerable  variety  of  appearances  have 
been  believed  to  represent  transitional  stages  between  secreting  acini 
and  islands  of  Langerhans.  The  island  of  Langerhans  is  usually  out- 
lined by  a  delicate  circle  of  connective  tissue,  but  frequently  the  outline 
L=  less  sharp  and  the  shape  of  the  body  is  modified  by  encroachment  of 

"*  Chiari :    Zeit.  f .  Heilk.,  1896,  xvii,  69. 

^  Statkewitsch :    Arch,  f .  exper.  Path.  u.  Phar.,  1894,  xxxiii,  415. 
"  Vincent    and    Thompson :     Internat.    Monatsschr.    f .    Anat.    u. 
Physiol.,   1907,   xxiv,   61. 

="  Jarotzky :    Virchow's  Arch.,  1899,  clvi,  409. 


HISTOLOGY  OF  THE  PANCREAS  73 

neighboring  acini;  an  acinus  is  occasionally  found  within  the  area 
of  an  intoracinar  island.  Continuity  between  the  cellular  columns  of 
the  island  of  Langerhans  on  the  one  hand  and  secreting  acini  on  the 
other  has  been  described  by  a  number  of  hlstologists,  but  others  have 
maintained  that  close  contact  explains  the  apparent  continuity. 

In  reptiles  and  in  birds,  columns  of  the  islands  of  Langerhans  are 
frequently  found  continuous  with  the  wall  of  secreting  acini;  in  the 
rabbit  Dewitt  has  traced  the  continuity  in  a  reconstructed  model. 
Since  the  islands  of  Langerhans  and  the  secreting  acini  have  a  common 
origin,  it  is  not  improbable  that  they  remain  continuous  in  the  adult 
organ.  Both  Pearce  and  Koster  have  shown  that  the  islands  of  Langer- 
hans in  human  embryos  are  connected  with  the  tubules  of  the  gland 
by  a  stalk  of  cells;  atrophy  of  this  stalk  and  complete  independence 
of  islands  is  demonstrable  in  embryos  three  months  old. 

There  is  little  doubt  that  some  authors  have  described  as  islands 
of  Langerhans  acini  within  which  centro-acinar  cells  are  unusually 
numerous.  Dale  differs  from  all  histologists  who  have  studied  structure 
and  histogenesis  of  the  pancreas  in  asserting  that  centro-acinar  cells 
may  represent  a  transitional  stage  between  secreting  cells  and  cells  of 
interaeinar  islands. 

In  the  normal  human  pancreas  one  occasionally  finds  groups  of 
acini  composed  of  cells  suggesting  a  transition  ^  from  the  secreting 
acini  to  island  of  Langerhans.  The  cell-protoplasm  does  not  take 
the  nuclear  dye  as  does  the  basal  part  of  the  ordinary  glandular  cell, 
and  when  stained  with  eosin  has  a  bright  pink  color  and  homogeneous 
refractive  appearance.  The  nucleus,  which  shows  no  evidence  of  de- 
generative change,  is  situated  near  the  centre  of  the  cell.  Occasionally 
one  or  more  cells  of  the  character  described  form  part  of  an  acinus 
which  otherwise  resembles  those  about  it.  Usually,  however,  a  group 
of  acini  are  changed,  and  such  an  area  may  roughly  correspond  in  size 
to  an  island  of  Langerhans. 

It  is  probable  that  these  foci,  in  part  at  least,  represent  what 
Laguesse  and  Pischinger '"  and  perhaps  Lewaschew  have  described  as 
stages  of  transition.     The  arrangement  of  more  or  less  columnar  cells 

''  Opie :    Loc.  cit.,  p.  62. 

'^  Pischinger:    Inaug.  Diss.,  Munich,  1895. 


74  DISEASE  OF  THE  PANCREAS 

about  a  central  lumen  is,  however,  still  presen'ed,  and  similar  areas 
in  which  this  arrangement  is  lost  are  not  found.  The  lumen,  indeed, 
is  usually  very  conspicuous  and  is  often  considerably  dilated,  filled 
with  products  of  secretion  which  stain  deeply  with  eosin.  It  seems 
probable  that  these  groups  of  acini  are  altered  as  the  result  of  peculiar 
functional  aetivitj'^,  it  may  be  of  hyperstimulation  of  the  gland.  There 
is  at  least  no  evidence  that  they  represent  transitional  stages  between 
glandular  acini  and  islands  of  Langerhans. 

Such  altered  acini  are  observed  in  a  small  proportion  of  normal 
glands.  They  have  been  found  in  three  of  twenty-seven  glands  exam- 
ined carefully  for  their  presence.  -  They  have  been  present,  moreover,  * 
in  three  of  seven  relatively  normal  organs  from  diabetic  patients.  The 
occurrence  of  voracious  appetite  and  increased  food  ingestion  in  indi- 
viduals so  affected  may  explain  the  occuirence  of  these  areas  which 
represent  possibly  foci  of  peculiar  secretory  activity. 

The  diversity  of  the  opinions  concerning  the  struc- 
tures under  consideration  has  justified,  I  believe,  the 
preceding  detailed  discussion  of  their  nature.  Certain 
facts  may  be  considered  established.  The  islands  of 
Langerhans  are  composed  of  cells  of  epithelial  type  hav- 
ing the  same  origin  as  those  which  form  the  acini ;  disap- 
pearance of  the  connection  between  the  two  structures 
may  be  observed  during  embryonic  life.  Ramifications 
of  the  pancreatic  duct  on  the  one  hand  do  not  penetrate 
the  interacinar  islands,  while  on  the  other  hand  these 
bodies  have  an  intimate  relation  to  the  vascular  system. 
They  occupy  a  definite  position  within  the  pancreatic 
lobule  (of  the  cat),  and  are  more  numerous  in  certain 
parts  of  the  gland  than  in  others.  They  have  a  frame- 
work of  connective  tissue  and  a  vascular  supply  which 
differs  from  that  of  the  secreting  acini.  Conflicting  ex- 
perimental evidence  furnishes  no  proof  that  secreting 
acini  mav  be  transferred  into  islands  of  Langerhans  and 


HISTOLOGY  OF  THE  PANCREAS  75 

the  various  so-called  transitions  between  the  two  struc- 
tures retain  the  characters  of  secreting  acini.  The  cells 
of  the  islands  of  Langerhans  contain  fine  granules  which 
differ  in  physical  and  chemical  properties  from  the 
zymogen  granules  of  the  secreting  acini. 

The  function  of  the  islands  of  Langerhans  has  been 
the  subject  of  much  speculation;  that  which  has  been 
based  upon  false  interpretation  of  their  anatomy  has  no 
present  interest,  and  their  supposed  relation  to  the 
lymphatic  system  will  not  be  discussed. 

The  intimate  relation  of  columns  of  epithelial  cells  to 
a  rich  capillary  network  has  suggested  that  the  islands 
of  Langerhans  furnish  some  substance  to  the  blood, 
the  hypothetical  internal  secretion  of  the  pancreas. 
Abundant  experimental  research  inaugurated  by  Von 
Mering  and  Minkowski  having  shown  that  the  pancreas 
exerts  an  important  influence  on  carbohydrate  metabo- 
lism, several  writers,  Laguesse,^*^  Schafer,*^  Diamare, 
and  others,  have  suggested  that  the  islands  of  Langer- 
hans perform  this  function.  Ssobolew  claims  to  have 
ol)tained  experimental  evidence  that  assimilation  of 
sugar  causes  changes  in  the  cells  of  these  bodies  com- 
parable to  those  which  occur,  as  Heidenhain  has  shown, 
in  the  secreting  cells  as  the  result  of  increased  func- 
tional activity.  The  cells  of  the  interacinar  islands  are, 
he  states,  more  granular  after  hunger  which  has  lasted 
tTvo  or  three  days,  but  after  feeding  with  carbohydrates 
in  considerable  quantity,  or  after  intravenous  injection 
of  sugar,  the  granules  within  the  cells  diminish  in  num- 

*"  LagTiesse :    Compt.  rend.  Soc.  de  biol.,  1893,  xlv,  819. 
"Schafer:    British  Med.  Jour.,  1895,  ii,  341. 


76      '  DISEASE  OF  THE  PANCREAS 

ber.  Schmidt,^-  however,  has  been  unable  to  produce 
similar  phenomena  in  mice  and  in  guinea-pigs  after  in- 
traperitoneal and  intravenous  injection  of  solutions  of 
sugar. 

The  study  of  pathological  changes  associated  with  the 
disease  of  carbohydrate  metabolism,  diabetes  mellitus, 
has  shown  that  the  islands  of  Langerhans  control  the 
assimilation  of  sugar.  It  will  be  the  purpose  of  a  subse- 
quent chapter  to  define  the  relationship  of  diabetes  mel- 
litus to  diseases  of  the  pancreas  and  to  alterations  of  the 
islands  of  Langerhans. 


Schmidt:    Munchener  med.  Woch.,  1902,  xlix,  51. 


CHAPTER  IV. 

THE    PANCREAS    AND    DIGESTION. 

To  study  the  pancreatic  juice  unmixed  with  intestinal 
contents,  and  to  determine  the  conditions  which  influence 
its  flow,  it  is  necessary  to  collect  the  secretion  as  it 
escapes  from  the  duct  of  the  gland.  Shortly  after  the 
discovery  of  the  pancreatic  duct  by  Wirsung,  Eegius  de 
Graaf  produced  a  pancreatic  fistula  in  the  dog  and  col- 
lected pancreatic  juice  through  a  tube  fixed  in  the  duct. 
In  his  work,  '  ^  De  natura  et  usu  succi  pancreatici, ' '  pub- 
lished in  1664,  he  pictures  an  animal  with  both  pancreatic 
and  salivary  fistulas. 

Pancreatic  Fistula. — It  has  long  been  known  that  the 
operation  necessary  for  the  insertion  of  a  cannula  into 
the  pancreatic  duct  causes  such  profound  disturbance  of 
the  gland  that  flow  of  pancreatic  juice  ceases  for  a  time. 
AVhen  a  cannula  is  fixed  in  the  duct  secretion  begins  after 
one  or  two  days,  but  irritation  of  the  gland  causes  a 
continuous  flow  of  thin  fluid,  and  pathological  changes 
soon  occur  in  the  gland.  Pawlow  ^  in  1879  first  showed 
that  these  difficulties  might  be  overcome  by  transplanting 
into  the  abdominal  wall  the  duodenal  end  of  the  pancre- 
atic duct,  together  with  the  mucosa  of  the  duodenum 
immediately  about  it.  The  gland  remains  normal;  pan- 
creatic juice  may  be  collected  by  suitable  means,  and 
conditions  which  influence  its  amount  and  character  may 
be  studied.     The  success  of  the  experiment  is  dependent 

^Pawlow:  The  Work  of  the  Digestive  Glands   [Ti'ans.],  London, 
1902. 

77 


78  DISEASE  OF  THE  PANCREAS 

upon  certain  precautions.  Contact  with  escaping  pan- 
creatic juice  causes  maceration  and  erosion  of  the  skin 
in  contact  with  the  wound,  so  that  the  animal  must  lie 
upon  some  absorbent  material,  such  as  sawdust  or  sand. 
Loss  of  pancreatic  juice,  it  is  believed,  may  have  an 
unfavorable  influence  upon  the  animal,  so  that  conditions 
which  diminish  the  activity  of  secretion  are  desirable. 
Upon  a  diet  of  milk  and  bread  with  addition  of  sodium 
carbonate,  which  perhaps  replaces  the  alkali  lost  in  the 
pancreatic  juice,  an  animal  may  be  kept  in  good  health 
according  to  Starling^  during  months  or  even  years. 

PANCREATIC  JUICE  AND  ITS  ENZYMES. 

Pancreatic  juice  is  a  clear  watery  fluid.  The  com- 
position of  pancreatic  juice  obtained  from  fistulas  remain- 
ing after  operations  upon  the  pancreas  in  man  differs 
little  from  that  obtained  from  the  dog  by  the  method 
just  described.  The  specific  gravity  is  only  slightly 
greater  than  that  of  water  (1.0075-1.0098) ;  water  forms 
approximately  98.5  and  solids  1.5  per  cent.,  from  a  third 
to  two-thirds  of  solids  being  ash.  Pancreatic  juice  con- 
tains a  small  quantity  of  coagulable  protein  and  certain 
enz3^mes  which  it  is  well  known  have  an  important  part 
in  the  digestion  of  protein,  fat,  and  carbohydrates. 

Experiments  upon  the  secretion  of  pancreatic  juice 
have  been  performed  in  large  part  upon  the  dog.  In 
this  animal  the  gland  is  inactive  when  food  is  withheld, 
but  immediately  after  a  meal  secretion  begins,  reaching 
a  maximum  during  the  following  three  hours.    Walther  -^ 


Starling:  Phj'siology  of  Digestion,  Chicago,  1906. 
Walther:  Arch,  de  scien.  biol.,  1899,  vii,  1. 


THE  PANCREAS  AND  DIGESTION 


79 


has  shown  that  the  quantity  and  the  character  of  the 
pancreatic  juice  varies  with  the  character  of  the  food. 
The  following  table  shows  the  effect  of  different  diet — 
namely,  600  c.c.  of  milk,  250  Gm.  of  bread,  or  100  Gm. 
of  meat — upon  the  secretion  of  pancreatic  juice: 


Food  ingested. 

Quantity  of 

pancreatic 

juice. 

Duration  of 
secretion. 

Per  cent,  of 

organic 
substance. 

Per  cent, 
of  ash. 

Alkalinity 
of  ash  as 

per  cent,  of 

sod.  carb. 

in  100  c.c. 
of  juice. 

600  c.c  milk 

250  grammes  bread 

100  grammes  meat 

c.c. 

45.7 

162.4 

131.6 

hrs.  min. 

4     30 
7     35 
4     12 

4.399 
2.298 
1.558 

0.869 
0.925 
0.907 

0.348 
0.564 
0.588 

Meat  has  caused  rapid  secretion  of  juice  relatively 
poor  in  solids  whereas  bread  has  caused  slower  secretion 
of  a  somewhat  greater  quantity  of  juice.  Milk  has  ex- 
cited the  flow  of  a  small  quantity  of  more  concentrated 
juice  of  which  the  alkalinity  is  relatively  low. 

Secretion  of  Pancreatic  Juice;  Secretin. — The  maxi- 
mum activity  of  pancreatic  secretion  occurs  at  a  time 
when  the  stomach  is  discharging  its  contents  into  the 
duodenum,  and  there  is  abundant  evidence  that  the  gland 
is  excited  to  activity  during  digestion  by  passage  of  the 
acid  chyme  over  the  mucous  membrane  of  the  duodenum. 
Experiments  of  Pawlow  have  shown  that  weak  hydro- 
chloric acid  causes  an  almost  immediate  flow  of  juice: 
sOther  acids — e.g.,  water  saturated  with  carbonic  acid 
gk^ — have  the  same  effect,  but  alkalies  inhibit  secretion, 
perhaps,  only  because  they  neutralize  the  acid  of  the 
stomach.  Neutralization  of  the  gastric  contents  during 
digestion  prevents  the  flow  of  pancreatic  juice  which 
follows  ingestion  of  food. 


80  DISEASE  OF  THE  PANCREAS 

Much  effort  has  been  made  to  determine  the  means  by 
which  stimulation  of  the  duodenal  mucosa  excites  the 
pancreas  to  activity,  and  the  investigations  of  Bayliss 
and  Starling^  have  recently  furnished  an  adequate  ex- 
planation. Analogy  with  the  salivary  glands  has  sug- 
gested that  secretion  occurs  as  the  result  of  a  nervous 
reflex,  and  Pawlow  ^  has  succeeded  in  producing  a  flow  of 
pancreatic  juice  by  stimulation  of  both  the  vagus  and 
splanchnic  nerves.  Nevertheless,  Wertheimer  and  Le- 
page*^ have  shown  that  the  flow  of  pancreatic  juice  ex- 
cited by  the  presence  of  acid  in  the  duodenum  occurs 
after  division  of  the  vagus  and  after  excision  of  the 
sjTupathetic  nerves. 

The  experiments  of  Bayliss  and  Starling  have  con- 
clusively demonstrated  that  acid  applied  to  the  intes- 
tinal mucosa  may  cause  pancreatic  secretion  in  the  ab- 
sence of  any  nervous  connection  between  intestine  and 
jDancreas.  Wertheimer  and  Lepage  ^  had  found  that  acid 
caused  a  maximum  flow  when  introduced  into  the  duode- 
num, whereas  the  response  diminished  when  acid  was  in- 
troduced into  the  lower  parts  of  the  intestine  and  disap- 
peared when  the  lowermost  part  of  the  ileum  was 
reached.  Baj^liss  and  Starling  ligated  the  two  ends  of 
a  loop  of  the  upper  part  of  the  jejunum,  and  destroyed 
its  nervous  connection  with  other  organs  by  dividing 

'  Bayliss  and  Starling :  Jour,  of  Physiol.,  1902,  xxviii,  325 ;  1903, 
xxix,  174. 

'  Pawlow :  Arch,  f .  Anat.  u.  Physiol.,  1893,  Siippl.,  Physiol.  Abt,, 
176. 

*  Wertheimer  and  Lepage :  (Jompt.  rend.  Soc.  de  biol.,  1899,  li, 
951. 

'  Wertheimer  and  Lerpage :  Jour,  de  physiol.  et  de  path,  gen , 
1901,   iii,   335. 


THE  PANCREAS  AND  DIGESTION  81 

splanchnics  and  vagi,  extirpating  the  abdominal  sympa- 
thetic ganglia  and  dissecting  away  all  nervous  filaments 
which  follow  the  blood-vessels.  Although  the  loop  was 
connected  with  the  rest  of  the  body  only  by  its  blood- 
vessels, introduction  of  hydrochloric  acid  caused  an  abun- 
dant flow  of  pancreatic  juice.  Some  chemical  substance 
transported  by  the  blood  from  the  intestinal  loop  to  the 
pancreas  had  caused  the  gland  to  secrete. 

Since  acid  introduced  into  the  blood  did  not  excite 
pancreatic  secretion,  Bayliss  and  Starling  suspected  that 
acid  introduced  into  the  intestine  might  cause  the  intes- 
tinal mucosa  to  elaborate  some  substance  capable  of 
exciting  the  pancreas  to  activity,  when  absorbed  by  the 
blood.  This  hypothesis  was  confirmed  when  they  found 
that  the  epithelial  cells  of  the  intestinal  mucosa  treated 
with  acid  yielded  an  extract  which,  when  introduced  into 
the  circulation,  caused  active  flow  of  pancreatic  juice. 
The  substance  named  by  Bayliss  and  Starling  secretin, 
is  not  present  in  the  cells  of  the  mucosa,  and  an  extract 
prepared  from  them  is  incapable  of  stimulating  the  pan- 
creas ;  these  cells  contain  a  substance,  prosecretin,  which 
is  converted  by  acid  into  secretin. 

Pawlow  *  has  been  unwilling  to  admit  that  nervous 
reflex  has  no  part  in  the  mechanism  of  pancreatic  secre- 
tion. He  does  not  think  that  the  secretion  caused  by 
stimulation  of  the  vagus  is  wholly  referable  to  movements 
of  the  stomach  forcing  acid  contents  into  the  duodenum. 
As  evidence  of  direct  influence  of  the  vagus  upon  the 
gland,  he  points  out  that  pancreatic  juice  obtained  by 

*  Pawlow :    Nagel's  Handb.   der  Physiol,   des  Mensehen.,  Braun- 
schweig, 1907,   ii,  p.   6G6. 
6 


82  DISEASE  OF  THE  PANCREAS 

stimulation  of  the  vagus  is  much  more  concentrated  than 
that  obtained  by  action  of  acid  upon  the  duodenum; 
atropine,  moreover,  paralyzes  this  action  of  the  vagus, 
whereas  it  has  no  effect  upon  secretion  caused  by  acid. 

It  is  noteworthy  that  substances  other  than  acid 
applied  to  the  duodenal  mucosa  may  excite  pancreatic 
secretion.  Fats  and  soap  stimulate  secretion,  but  their 
action  is  much  less  intense  than  that  of  acid  (Fleig  *). 

Trypsin,  Trypsinogen,  and  Enterohinase. — Pepsin 
forms  albumoses  and  peptones  from  protein,  but  simpler 
products  such  as  amino-acids  are  formed  only  by  pro- 
longed action  of  the  enzyme ;  with  the  proteolytic  enzyme 
of  the  pancreatic  juice — namely,  trypsin — hydrolysis  of 
protein  is  more  complete  and  peptones  are  transformed 
into  amido-acids.  The  action  of  trypsin  is  most  power- 
ful in  the  presence  of  a  weakly  alkaline  solution ;  sodium 
carbonate  in  0.2  to  0.3  per  cent,  solution  is  favorable  to 
its  action.  Heidenhain  *  found  that  the  greater  the  con- 
centration of  trypsin  the  greater  was  the  concentration 
of  alkali  necessary  for  its  optimum  activity.  Trypsin  is 
readily  destroyed  by  heat,  and  purified  solutions  lose 
their  activity  at  a  temperature  of  from  45°  to  50°  after  a 
few  minutes,  but  the  presence  of  protein,  peptones  and 
various  salts  serve  to  protect  the  enzyme  so  that  it  with- 
stands much  higher  temperatures. 

The  serum  of  the  blood  has  the  power  to  inhibit  the 
action  of  trypsin  (M.  Hahn  ^) ;  this  anti-enzyme  is  precipi- 

*  Fleig:    Jour,  de  physiol.  et  de  path,  gen.,  1904,  vi,  32,  50. 
"  Heidenhain :  Beitrage    zur    Kenntniss    des    Pankreas,    Pfliiger's 
Arch.,  1875,  x,  557. 

"  Hahn,  M. :  Berliner  klin.  Woeh.,  1897,  xxxiv,  499. 


THE  PANCREAS  AND  DIGESTION  83 

tated  with  tlie  albumin  fraction  of  the  serum  and  is 
absent  in  the  globulin  fraction.     It  is  destroyed  by  heat. 

Trypsin  does  not  exist  within  the  secreting  cells  of  the 
pancreas,  and  extracts  made  from  the  fresh  gland  do  not 
act  upon  protein.  Heidenhain  has  found  that  the  gland 
treated  with  acid  yields  an  active  extract,  for  trypsino- 
gen,  the  precursor  of  the  enzyme,  is  transformed  into 
trypsin.  Pawlow  has  shown  that  juice  obtained  from  a 
pancreatic  fistula  contains  trypsinogen  and  his  pupil,  Che- 
powalnikow,^"  has  made  the  important  discovery  that 
intestinal  juice  has  the  power  to  increase  enormously 
the  proteolytic  activity  of  pancreatic  juice. 

Succus  entericus  contains  a  substance,  enterokinase, 
which  transforms  inactive  trypsinogen  of  the  pancreatic 
juice  into  active  trypsin.  A  small  quantity  of  entero- 
kinase is  capable  of  converting  a  large  quantity  of  tryp- 
sinogen into  trypsin.  This  substance,  which  is  readily 
destroyed  by  heat  (67  to  70°  C),  is,  according  to  Paw- 
low,  an  enzyme — an  enzyme  which  acts  upon  another 
enzyme.  It  is  produced  only  by  the  intestinal  mucous 
membrane  and,  Pawlow  thinks,  in  response  to  a  definite 
stimulus.  A  tube  inserted  into  an  isolated  intestinal 
loop  excites  a  flow  of  fluid  which,  with  repeated  with- 
drawal, contains  less  and  less  enterokinase  until  finally 
none  is  present;  the  introduction  of  a  small  quantity  of 
pancreatic  juice  causes  the  secretion  of  a  fluid  containing 
much  kinase  but  boiled  pancreatic  juice  has  no  such 
effect.  The  presence  of  trypsinogen  causes  the  mucous 
membrane  to  produce  the  activating  substance. 

"  Chepowalnikow :  The  Physiology  of  Sueeus  Entericus.  Inaug. 
Diss.,  St.  Petei-sbi^rg,  1899.     Quoted  by  Pawlow. 


84  DISEASE  OF  THE  PANCREAS 

According  to  Starling  the  pancreas  contains  only 
trypsinogen,  and  the  spontaneous  occurrence  of  trypsin 
is  due  to  accidental  contamination  with  intestinal  con- 
tents; the  juice  which  is  obtained  from  the  pancreatic 
duct  by  the  use  of  secretin  contains  only  trypsinogen. 
Pawlow,  on  the  contrary,  has  claimed  that  the  juice 
obtained  from  a  permanent  fistula  in  a  dog  which  has 
been  fed  on  an  exclusive  diet  of  meat  contains  active 
trypsin. 

The  pancreatic  juice  or  extracts  from  the  pancreas 
exhibit  certain  properties  which  are  referred  by  some 
observers  to  the  action  of  trypsin,  whereas  others  believe 
that  they  are  due  to  separate  enzymes.  Nucleic  acid  is 
in  great  part  precipitated  in  the  stomach  but  it  is  dis- 
solved in  the  intestine.  Solution  of  nucleic  acid  which  is 
doubtless  caused  by  pancreatic  juice  has  been  attributed 
to  an  enzyme,  nuclease,  present  in  the  pancreatic  juice 
(Umber  ^1).  The  power  of  the  pancreas  to  coagulate 
casein  observed  by  Ktihne,  and  believed  to  indicate  the 
presence  of  a  lab-ferment,  has  been  regarded  by  some 
observers  as  a  property  of  trypsin. 

Steapsin. — The  fat-splitting  enzyme  of  the  pancreas, 
steapsin,  acts  well  in  the  presence  of  an  alkaline,  neutral, 
or  acid  reaction.  It  is  not  only  capable  of  splitting  neu- 
tral fats  into  glycerin  and  fatty  acids,  with  formation 
of  soaps  when  alkali  is  present,  but  can  decompose  a 
considerable  number  of  esters  of  lower  fatty  acids  such 
as  ethyl-butyrate.  When  this  substance  is  used  as  a  test 
for  the  presence  of  fat-splitting  enzyme  the  amount  of 
acid  formed  measures  the  activity  of  the  enzyme.    Kastle 


"Umber:  Zeit.  f.  klin.  Med.,  1901,  xliii,  282. 


THE  PANCREAS  AND  DIGESTION  85 

and  Loevenhart  ^2  j^^ve  shown  that  the  action  of  the 
enzyme  is  reversible;  the  addition  of  a  glycerin  extract 
of  pancreas  to  a  solution  of  butyric  acid  and  ethyl-alcohol 
causes  the  formation  of  ethyl-butyrate. 

Steapsin  occurs  in  the  pancreas  as  zymogen ;  the  pan- 
creatic juice  contains  some  active  steapsin.  Bile  in- 
creases the  activity  of  the  fat-splitting  enzyme  two-  or 
three-fold  (Nencki,^"  Bruno  ^^)  but  its  mode  of  action  is 
not  understood,  for  the  bile  contains  no  substance  analo- 
gous to  enterokinase. 

Amylopsin. — The  amylolytic  enzyme  of  the  pancreas 
forms  from  starch  dextrin  and,  finally,  maltose ;  invertin 
is  not  produced  by  the  pancreas  and  little  if  any  dextrose 
is  formed  from  starch  by  the  action  of  pancreatic  juice. 
Asa  measure  of  the  activity  of  amylopsin,  Pawlow  has 
used  small  tubes  filled  with  starch  paste;  the  length  of 
the  column  dissolved  at  each  end  varies  with  the  quantity 
of  enzyme  which  is  present.  The  enzyme  acts  in  the 
presence  of  weak  acid  and  is  slightly  inhibited  by  weak 
alkali.  According  to  Zweifel  ^^  there  is  no  amylopsin  in 
the  pancreas  of  the  new-born  infant,  and  it  is  not  found 
until  more  than  a  month  after  birth. 

Self -Digestion  of  the  Pancreas. — The  pancreas  at  au- 
topsy is  frequently  found  to  have  undergone  changes 
which  do  not  occur  in  other  organs  and  are  doubtless 
referable  to  the  proteolytic  enzyme  which  it  contains. 
From  a  study  of  seventy-five  cases,  Chiari  ^^  has  reached 

^  Kastle  and  Loevenhart :  American  Chem.  Jour.,  1900,  xxiv,  491. 
''Nencki:  Arch.  f.  exper.  Path.  u.  Pharm.,  1886,  xx,  367. 
"Bruno:  Arch,  des  seien.  bioL,  1899,  vii,  87. 
'°  Zweifel :    Verdauungsapparat  Neugeborener,  Strassburg,  1874. 
'"  Chiari :  Zeit.  f .  Heilk.,  1896,  xvii,  69. 


86  DISEASE  OF  THE  PANCREAS 

the  conclusion  that  in  about  one-half  of  all  subjects  the 
pancreas  at  the  time  of  death  has  the  capabilit}^  of 
causing  digestion  of  its  own  substance.  This  condition 
of  self-digestion  may  be  observed  in  autopsies  performed 
only  a  few  hours  after  death,  and  has  no  relationship 
to  putrefaction,  from  which  it  can  be  readily  distin- 
guished. The  conditions  upon  which  it  depends  are  not 
known. 

Advanced  self-digestion  affects  the  entire  substance 
of  the  organ,  which  becomes  flaccid  in  consistence;  and 
in  sections  prepared  for  microscopic  examination  nuclei 
are  unstained,  so  that  the  tissue  has  a  homogeneous 
appearance.  The  change  affects  the  interstitial  tissue 
as  well  as  the  secreting  parenchyma.  In  many  instances 
self-digestion  is  limited  to  small  areas.  When  the  organ 
undergoes  putrefaction,  nuclear  substance,  on  the  con- 
trary, is  not  dissolved,  but,  being  fragmented,  appears 
as  fine  particles  scattered  throughout  the  tissue  and  bac- 
teria can  be  readily  found. 

Disappearance  of  nuclei  with  self-digestion  of  the 
gland  is  probably  referable  to  trypsin,  which  quickly 
attacks  nucleic  acid.  The  minute  foci  of  fat  necrosis 
which  are  found  in  association  with  self-digestion  are 
perhaps  caused  by  post-mortem  action  of  the  fat-splitting 
enzyme  of  the  gland  (Wells  ^'^). 

The  occurrence  of  extravasated  blood  in  areas  of 
self -digestion  in  seven  of  seventy-five  cases  of  Chiari 
has  suggested  that  pancreatic  autolysis  may  occasionally 
occur  during  the  death  agony.  Such  extravasation, 
which  sometimes  extends  into  the  tissue  immediately 

"Wells:    Jour,  of  Med.  Research,  1903,  ix,  70. 


THE  PANCREAS  AND  DIGESTION  87 

about  the  gland,  may  give  the  organ  a  hemorrhagic  ap- 
pearance and  in  some  instances  has  doubtless  caused  an 
erroneous  diagnosis  of  acute  hemorrhagic  pancreatitis. 
The  flaccid  gland  with  scattered  foci  of  hemorrhage  has 
little  resemblance  to  the  lesion  of  hemorrhagic  necrosis 
(acute  hemorrhagic  pancreatitis). 

DISTURBANCES   OF  DIGESTION  CAUSED  BY  ABSENCE  OF 
PANCREATIC  JUICE  IN  THE  INTESTINE. 

Symptoms  which  follow  impairment  of  the  digestive 
or  external  function  of  the  pancreas  have  not  been  very 
clearly  defined,  and  though  certain  facts  have  been  estab- 
lished, clinical  observations  have  had  divergent  results. 
The  pancreatic  juice  contains  enzymes  which  aid  in  the 
digestion  of  proteins,  fats,  and  carbohydrates,  yet  it  is 
not  the  only  secretion  concerned  in  the  digestion  of  any 
one  of  these  substances.  Impaired  assimilation  of  pro- 
teins and  fats  is  more  readily  recognized  than  alterations 
affecting  the  digestion  of  carbohydrates,  and  hence  have 
been  assigned  greater  diagnostic  significance. 

Experimental  Studies. — Claude  Bernard  ^^  destroyed 
the  pancreas  of 'dogs  by  injecting  oil  of  other  bland  sub- 
stance into  the  larger  duct,  and  observed  that  the  faeces 
contained  in  abundance  food  material  which  had  under- 
gone little  change — for  example,  undigested  muscle- 
fibres  or  even  large  pieces  of  meat,  together  with  fat,  at 
times  in  such  quantity  that  when  cold  it  congealed  as  a 
layer  covering  the  surface  of  the  fecal  mass.  Subsequent 
observers  have  studied  by  somewhat  more  accurate 
methods   the   disturbances   which   Claude   Bernard  de- 

" Bernard,  Claude:  M^moire  sur  le  pancreas,  Compt.  rend,  de 
I'Acad.  des  sciences,  Suppl.,  1856. 


88  DISEASE  OF  THE  PANCREAS 

scribes.  Abelmann  ^^  found  after  removing  the  pancreas 
in  dogs  that  all  fat  taken  with  the  food  reappeared  in 
the  faeces;  an  exception  was  the  emulsified  fat  of  milk, 
of  which  only  about  47  per  cent,  reappeared.  Under 
normal  conditions  little  more  than  5  per  cent,  of  fat 
escapes  absorption.  Hedon  and  Ville  -'^  claim  that  the 
statement  of  Abelmann  is  somewhat  exaggerated;  they 
have  found  that  some  fat  which  is  not  emulsified  may 
undergo  absorption  even  when  the  gland  is  completely 
removed,  only  about  82  per  cent,  reappearing  in  the 
faeces.  After  partial  extirpation  only  half  the  fat  in 
gested  is  unabsorbed.  After  complete  removal  of  the 
organ,  according  to  Abelmann,  fat  is  still  split,  and  about 
four-fifths  of  that  which  is  unused  is  represented  in  the 
faeces  by  fatty  acids. 

In  the  experiments  of  Abelmann  after  total  excision 
of  the  pancreas  about  56  per  cent,  of  the  proteins  in- 
gested has  escaped  absorption,  while  after  partial  re- 
moval 46  per  cent,  has  escaped.  Under  normal  condi- 
tions not  more  than  one  or  two  per  cent,  of  nitrogenous 
material  is  unabsorbed.  Loss  of  the  pancreas  also  alters 
the  normal  digestion  of  carbohydrates,  and,  according 
to  Abelmann,  20  to  40  per  cent,  of  starch  may  reap- 
pear in  the  faeces,  having  undergone  no  transforma- 
tion into  sugar.  Subsequent  experimenters  have  con- 
firmed the  observations  of  Abelmann. 

After  partial  extirpation  of  the  pancreas  so  perfoi-med  that  the 
pancreatic  juice  no  longer  reaches  the  intestine,  Abelmann  found 
absorption  of  fat  much  more  active  than  after  complete  extirpation. 

"  Abelmann :   Inaug.  Diss.,  Dorpat,  1890. 

'"' Hedon  and  Ville:  Physiologic  du  i)aiK'rc'as,  Paris. 


THE  PANCREAS  AND  DIGESTION  89 

In  a  long  series  of  exiieriments  Ugo  Lombroso  ^'  has  compared  the 
effect  of  extirpation  with  that  of  operations  which  prevent  access  of 
pancreatic  juice  to  the  intestine.  He  has  found  in  the  faeces  after  re- 
moval of  the  gland  an  increased  percentage  of  the  ingested  protein, 
fat,  and  carbohydrates,  whereas  after  ligation  of  the  pancreatic  ducts 
or  after  permanent  removal  of  pancreatic  juice  by  way  of  a  Pawlow's 
fistula,  with  an  occasional  exception  there  has  been  unimpaired  digestion 
of  these  substances.  With  partial  removal  of  the  gland  so  performed 
that  the  secretion  of  the  part  remaining  no  longer  reaches  the  intestine, 
the  result  has  been  variable;  and  especially  when  degenerative  changes 
have  occurred  in  the  remaining  pancreatic  tissue,  an  abnormal  quantity 
of  undigested  protein  fat  and  carbohydrate  may  appear  in  the  faeces. 
Kleckseder"  has  partially  removed  the  pancreas  and  diverted  from 
the  intestine  the  secretion  of  the  glandular  tissue  which  remains;  there 
is  absorption  of  fat  from  the  intestine.  The  pancreas,  he  thinks,  fur- 
nishes an  internal  secretion  which  makes  possible  the  absorption  of 
fat  from  the  intestine. 

In  performing  experiments  just  mentioned  certain  errors  are 
possible.  It  is  necessary  to  occlude  both  ducts  of  the  pancreas.  With 
an  external  fistula  pancreatic  juice  may  return  to  the  intestinal  tract 
when  the  animal  licks  its  wound. 

Regeneration  of  a  pancreatic  duct  after  section  and  ligation  of 
both  duets  may  explain  some  of  the  discordant  observations  which  have 
been  described.  Visentini  ^*  found  such  regeneration  with  complete 
absence  of  functional  disturbance,  whereas  when  the  ducts  were  per- 
manently occluded  absorption  of  fat  was  impaired  so  that  from  50 
to  75  per  cent,  of  ingested  fat  reappeared  in  the  faeces. 

Disturbances  of  digestion  similar  to  those  which  fol- 
low experimental  extirpation  of  the  gland  have  been 
noted  in  human  cases  where  the  pancreas  has  been  par- 
tially destroyed  by  chronic  inflammation,  by  cysts,  or  by 

^^  Lombroso  :  Pflliger's  Arch.,  1906,  cxii,  531 ;  Arch,  f .  exper.  Path, 
u.  Pharm.,  1907,  Ivi,  357. 

''  Kleckseder :  Arch,  f .  exper.  Path.,  1908,  lix,  407. 
'■^Visentini:  Virchow's  Arch.,  1909,  cxev,  555. 


90  DISEASE  OF  THE  PANCREAS 

new  growths;  occlusion  of  the  duct  caused  by  calculi  or 
by  tumor  and  followed  by  degenerative  changes  in  the 
gland  may  have  the  same  effect.  Even  when  the  larger 
duct  is  obstructed  pancreatic  juice  may  still  reach  the 
intestine  througli  the  duct  of  Santorini  in  at  least  three- 
fourths  of  all  individuals  (see  p.  17),  and  in  many  cases 
digestion  proceeds  with  no  manifest  impairment. 

Azotorrhoea. — In  human  cases  disturbance  of  protein 
digestion  may  be  recognizable  by  the  presence  of  unal- 
tered muscle-fibres  in  the  fa?ces.  In  the  discharges  of  a 
patient  suffering  with  diabetes,  nes,^^  forty  years  ago, 
found  well-preserved  striated  muscle-fibres,  and  the  ad- 
ministration of  an  extract  made  from  the  pancreas  of  a 
calf  caused  their  disappearance.  Advanced  chronic  in- 
terstitial inflammation  with  atrophy  was  found  at 
autopsy.  Fitz  ^^  has  found  in  the  literature  of  the  sub- 
ject only  eight  cases  in  which  undigested  muscle-fibres 
in  the  faeces  have  been  associated  with  clearly  demon- 
strated pancreatic  disease. 

In  a  few  instances  disturbance  of  protein  digestion 
has  been  tested  by  quantitative  methods.  In  cases  of 
diabetes  possibly  due  to  lesions  of  the  pancreas  Hirsch- 
feld  26  recovered  in  the  faeces  32  per  cent,  of  the  nitro- 
genous material  ingested  with  the  food;  under  normal 
conditions  only  5  or  6  per  cent,  is  lost.  In  a  case  of 
Weintraud,^'  where  autopsy  demonstrated  the  presence 

^Fles:  Arch.  f.  hollandische  Beit.  z.  Natur-.  und  Heilk.,  1864,' 
iii,  187.     Quoted  by  Friedreich. 

^  Fitz :  Trans,  of  the  Cong,  of  American  Phys.  and  Surg.,  1903, 
vi,  36. 

'•  Hirschf eld :  Zeit.  f.  klin.  Med.,  1891,  xix,  294. 

"  Weintrand :  Untersuchungen  iiber  den  Stoffwechsel  in  Diabetes 
Mellitus,  1893. 


THE  PANCREAS  AND  DIGESTION  91 

of  advanced  chronic  interstitial  pancreatitis,  45.2 
per  cent,  of  proteins  ingested  reappeared  in  the  faeces. 
A  similar  case  is  reported  by  Zoja.^^ 

Sahli^has  devised  a  means  by  which  he  is  able,  he  believes,  to 
test  the  efficiency  of  protein  digestion  in  the  intestine.  Gelatin  cap- 
sules, sufficiently  hardened  in  formalin,  are  almost  unaffected  by  gastric 
digestion  but  are  rapidly  dissolved  by  pancreatic  juice.  If  such  a 
capsule  is  filled  with  iodoform,  the  urine  or  saliva  gives  a  reaction  for 
iodine  at  the  end  of  from  four  to  eight  hours.  Absence  of  reaction, 
or  its  delayed  appearance,  indicates,  according  to  Sahli,  an  impair- 
ment of  pancreatic  digestion,  provided  the  mobility  of  the  stomach  is 
normal. 

Intestinal  disturbances  may  impair  the  value  of  the  reaction  and 
with  diarrhoea  unchanged  capsules  may  be  passed  with  the  fseces. 
Sahli  cites  cases  of  pancreatic  disease  in  which  the  reaction  has  been 
obtained,  whereas  Fromme  ^''  cites  instances  in  which  it  has  failed. 

Adolph  Schmidt  ^^  has  suggested  that  the  disappearance  of  nuclei 
in  muscle-fibres  passed  with  the  faeces  may  be  used  as  a  test  for  the 
efficiency  of  pancreatic  digestion.  Since  nuclear  material  is,  he  main- 
tains,  undigested  in  the  stomach,  persistence  of  nuclei  indicates  defective 
pancreatic  digestion.  Slightly  fibrous  beef  is  cut  into  small  cubes  0.5 
cm.  across,  hardened  in  absolute  alcohol,  and  enclosed  in  silk  gauze. 
After  alcohol  has  been  removed  by  washing  in  water  during  three 
hours,  cubes  are  administered  together  with  food.  If  muscle  remains 
in  the  gauze  passed  with  the  faeces  it  is  examined,  after  teasing,  with 
the  aid  of  acetic  acid  or  methylene  blue,  or  is  hardened  and  stained  with 
nuclear  dyes.  Schmidt  found  that  muscle  so  prepared  did  not  lose  its 
nuclei  in  the  intestinal  canal  of  three  dogs  from  which  the  pancreas 
had  been  removed.     In   one   hundred   individuals   without   pancreatic 

="  Quoted  by  Oser,  Deutsche  Klinik,  1901,  p.  151. 

^  Sahli :  Deutsche  med.  Woch.,  1897,  xxiii,  6 ;  Lehrbuch  der  klin- 
ischen  Untersuchungs  methoden,  Leipzig,  1902. 

'"  Fromme :    Miinchener  med.  Woch.,  1901,  xlviii,  591. 

"  Schmidt,  A. :  Die  Funktionspriifung  des  Darmes  mittlest  der 
Probekost,  Weisbaden,  1908. 


92  DISEASE  OF  THE  PANCREAS 

disease,  and  in  two  cases  of  j^anereatic  disease  with  partial  destniction 
of  gland,  no  nuclei  were  found,  but  in  two  cases  in  which  autopsy 
showed  that  pancreatic  juice  failed  to  reach  the  intestine  nuclei  per- 
sisted. In  two  eases  of  Hemmeter,'^  one  with  pancreatic  cyst,  the  other 
with  stenosis  of  the  pancreatic  duet  caused  by  cholelithiasis,  nuclear 
digestion  was  absent  but  appeared  after  operation  had  relieved  the 
condition.  In  one  of  two  cases  of  pancreatic  disease,  on  the, one  hand, 
and  in  a  case  with  comi^lete  achylia,  on  the  other.  Button  Steele  ^  found 
persistence  of  nuclei  with  Schmidt's  test  and  has  formed  the  opinion 
that  its  presence  may  indicate  little  more  than  diminution  of  digestive 
power. 

Steatorrhcea. — As  early  as  1820  Kunzmann^^  ob- 
served fat  in  the  faeces  of  a  man  who  subsequently  died 
with  obstruction  of  the  duct  of  Wirsung  and  induration 
of  the  pancreas,  together  with  chronic  jaundice.  Fles, 
nearly  fifty  years  later,  described  the  case  of  a  diabetic 
whose  faeces  contained  abundant  fat;  when  an  emulsion 
made  from  the  pancreas  of  a  calf  was  administered,  fat 
disappeared  from  the  stools.  In  this  case  no  jaundice 
was  present.  A  considerable  number  of  similar  cases 
have  been  described,  but  in  many  other  instances  of  grave 
pancreatic  disease  no  decreased  absorption  of  fat  has 
been  observed.  Finding  jaundice  associated  with  pan- 
creatic disease  in  many  cases  where  fatty  evacuations 
have  indicated  impaired  assimilation  of  fat,  Miiller  ^'' 
has  attributed  the  symptom  to  coexisting  obstruction 
of  the  common  bile  duct.  Nevertheless,  experimental 
as  well  as  clinical  observations  leave  little  doubt  that 


^Hemmeter:  American  Med.,  1905,  ix,  393. 
"  Steele :  Univ.  of  Pennsylvania  Med.  Bull.,  1906,  xix. 
^'  Kunzmann,  cited  by  Friedi-cich :  Diseases  of  the  Pancreas,  Von 
Ziemssen's  Practice  of  Medicine   [Trans.],  New  York,  1878,  viii,  551. 
"'Miiller,  Fr.:  Zeit.  f.  klin.  Med.,  1887,  xii,  45. 


THE  PANCREAS  AND  DIGESTION  93 

steatorrhoea  may  follow  loss  of  the  pancreatic  secretion, 
and  a  review  of  cases  in  which  steatorrhoea  has  been 
associated  with  pancreatic  disease,  made  by  Fitz  in  1903, 
demonstrates  the  diagnostic  value  of  the  symptom  but 
shows  that  it  occurs  in  relatively  few  cases.  He  collected 
twenty-nine  instances  in  which  with  conclusive  evidence 
of  pancreatic  disease  there  were  fatty  stools;  in  seven- 
teen cases  there  was  no  jaundice,  the  lesion  of  the  gland 
being  tumor,  usually  cancer  (seven  cases),  calculi  (six 
cases),  cysts  with  atrophy  (two  cases),  or  a  lesion  desig- 
nated fatty  degeneration  (two  cases). 

The  relation  of  fat  in  the  stools  to  chronic  pancreatitis 
is  shown  by  observations  of  Eobson  and  Gammidge :  ^ 

Average  per  ct. 
of  fat  in  faeces. 

Chronic  pancreatitis  witli  obstruction  of  common  bile 
duct: 
18  cases  with  jaundice 43 

5  cases  with  no  jaundice 49 

Chronic   pancreatitis  with   no   obstruction   of   common 

bile  duct : 

6  cases  with  jaundice 60 

27  cases  with  no  jaundice 34 

Normal  individuals  (16  instances) 21 

In  some  cases  of  pancreatic  disease  free  fat  is  dis- 
charged with  the  faBces  as  an  oily,  yellow  fluid,  and  the 
condition  may  be  designated  true  steatorrhoea.  In  other 
cases  the  fseces  are  clay-colored  or  grayish-white,  often 
with  a  metallic  or  asbestos-like  appearance,  and  the  in- 
creased quantity  of  fat  is  demonstrable  only  by  micro- 

'°  Robson  and  Cammidge :  The  Pancreas,  Philadelphia  and  London, 
1907. 


94.  DISEASE  OF  THE  PANCREAS 

scopic  or  chemical  examination ;  such  stools  contain  neu- 
tral fats,  fatty  acids,  and  soaps. 

An  abnormally  large  amount  of  fat  in  the  intestinal 
discharges  is,  however,  by  no  means  characteristic  of 
pancreatic  disease,  and  may  even  appear  in  healthy  in- 
dividuals after  the  ingestion  of  very  great  quantities 
of  fat.  The  bile,  it  is  well  known,  is  essential  to  normal 
digestion  of  fats,  and  occlusion  of  the  bile  duct  is  a 
frequent  cause  of  fatty  stools.  Moreover,  the  absorption 
of  fat  is  prevented  by  certain  diseases  of  the  intestine, — 
for  example,  by  tuberculosis,  by  tuberculosis  of  the  mes- 
enteric glands,  and  even,  according  to  Nothnagel,^^  by 
extensive  catarrhal  inflammation  and  other  alterations 
accompanied  by  active  peristalsis.  It  is  only  in  the 
absence  of  such  conditions  that  the  presence  of  fat  is  an 
aid  to  the  diagnosis  of  pancreatic  disease. 

In  cases  of  pancreatic  disease,  according  to  Fr.  Miil- 
ler,  the  faeces  may  contain  a  diminished  proportion  of 
split-fat  although  the  total  fat  is  not  increased.  In  nor- 
mal faeces  from  20  to  30  per  cent,  of  fat  is  neutral  fat 
and  from  70  to  80  per  cent,  is  split-fat  occurring  as  fatty 
acids  and  soaps.  In  two  cases  of  pancreatic  disease 
studied  by  Miiller  split-fat  was  diminished  to  22.4  and 
47.2  per  cent,  respectively.  Fitz  has  collected  from  the 
literature  of  the  subject  seven  cases  of  undoubted  pan 
creatic  disease  without  jamidice  in  which  analyses  of 
fecal  fat  were  made  during  life.  Though  there  was  no 
steatorrhoea,  the  proportion  of  neutral  fat  was  normal 
or  less  than  normal  in  only  one  case,  and  averaged 
56.84  per  cent. 

"Nothnagel:  Erkrankungen  des  Darms  und  Peritoneum,  Handb. 
d.  spec.  Path.,  1895. 


THE  PANCREAS  AND  DIGESTION  95 

A  case  described  by  Walker  ^^  shows  that  fatty  stools 
may  be  passed  during  a  long  period  with  little  effect 
upon  nutrition,  A  man  passed  during  twenty  years 
colorless  stools  containing  oily  or  solid  fat  but  remained 
in  good  health,  actively  engaged  in  the  practice  of  medi- 
cine, and  died  at  the  age  of  ninety  years.  The  pan- 
creatic duct  was  occluded  by  a  calculus  and  the  gland 
was  almost  wholly  replaced  by  fat. 

Although  extirpation  of  the  pancreas  causes  disturb- 
ance of  digestion  of  carbohydrates  so  that  an  increased 
proportion  of  starch  ingested  with  the  food  reappears 
with  the  faeces,  determination  of  undigested  carbohy- 
drates has  been  seldom  made  and  has  acquired  no  signifi- 
cance for  the  diagnosis  of  pancreatic  disease. 

As  a  consequence  of  the  impaired  digestion  which 
results  when  pancreatic  juice  is  lost  or  greatly  dimin- 
ished in  amount,  much  of  the  food  material  taken  into 
the  digestive  tract  doubtless  passes  through  almost  un- 
changed. Oser  ^^  has  noted  the  voluminous  character  of 
the  fecal  discharges  in  cases  of  pancreatic  disease,  and 
has  emphasized  the  diagnostic  importance  of  this 
symptom. 

Pancreatic  Enzymes  in  Treatment  of  Digestive  Dis- 
turbances Referable  to  Absentee  of  Pancreatic  Juice  in 
Intestine. — Beneficial  results  have  in  a  few  instances 
attended  efforts  to  supply  by  artificial  means  a  deficiency 
of  digestive  enzymes  consequent  upon  disease  of  the  pan- 
creas. In  animals  it  has  been  found  possible  by  the 
administration  of  fresh  pancreas  to  increase  the  assimi- 

'' Walker:    Medico-Chir.  Trans.,  1889,  Ixsii,  257. 
^  Oser :   Die  Erkrankungen  des  Paxikreas.    Nothnagel's  Spec.  Path, 
u.  Ther.,  xvii,  Vienna,  1898. 


96  DISEASE  OF  THE  PANCREAS 

lation  of  protein  and  fat  impaired  by  extirpation  of 
the  pancreas.  Abelmann  has  found  that  pancreas  of 
the  pig  fed  to  dogs  from  which  the  organ  has  been  re- 
moved aids  the  absorption  of  fat,  and  so  favors  the 
digestion  of  protein  that  now  only  22  per  cent,  instead 
of  56  per  cent,  reappear  in  the  faeces.  These  observa- 
tions have  been  confirmed  by  Sandmeyer,*^  Rosenberg," 
and  others. 

The  remarkable  case  of  Fles  quoted  by  Friedreich  has  already  been 
mentioned;  disturbed  digestion  of  protein  and  fat  was  associated  with 
diabetes  mellitus.     The  fresh  pancreas  of  a  calf  was  inibbed  in  a  mor- 
tar with  six  ounces  of  water  and  the  mixture  strained.     A  part  of  the 
milky  fluid  obtained  was  taken  after  each  meal,  so  that  one  pancreas 
was  consumed  daily.     Though  the  patient  continued  upon  his  previous 
diet  of  bacon  and  fat  meat,  at  the  end  of  two  days  all  fat  had  disap- 
peared from  the  faeces  and  the  number  of  undigested  muscle-fibres  was 
greatly  diminished.     Whenever  the  administration  of  the  infusion  was 
discontinued   fat   and   muscle-fibres   reappeared.     Although   glycosuria 
persisted  unchanged,   the  general  condition  of  the  patient  improved 
for  a  time,  but  death  finally  occurred  as  the  result  of  phthisis.     The 
pancreas  was  the  seat  of  advanced  sclerosis.     Improved  assimilation  of 
fat   after  administration   of  fresh   pancreas   has   been   observed   in   a 
somewhat  similar  case  by  Masuyama  and  Schild.*^     In  a  case  recorded 
by  Langdon-Downs "   fatty   diarrha'a   was   controlled   by   the   use   of 
pancreatic   extract;   the   urine   contained   a  trace   of   sugar,   but  the 
condition  of  the  pancreas  could  not  be  learned  with  certainty.     Oser 
describes  a  case  m  which  a  tumor  mass  felt  in  the  epigastrium  was 
accompanied  by  jaundice;  in  the  faeces  were  found  undigested  muscle'- 
fibres  and  fat.     A  diagnosis  of  carcinoma  of  the  pancreas  was  made. 


*"Sandmeyer:  Zeit.  f.  Biol.,  1895,  xxxi,  12. 

"Rosenberg:  Arch.  f.  Anat.  u.  Pliysiol.,  1896;  Physiol.  Abt.,  535. 

"^  Masuyama  and  Schild :    Zeit.  f .  diat.  u.  physik.  Ther.,  1899,  iii, 

451. 

"  Langdon-DoTATis :  Trans,  of  the  Clin.  Soc.  of  London,  1869,  ii,  119. 


THE  PANCREAS  AND  DIGESTION  97 

The  administration  of  panereatin  (Merck),  one  gramme  every  day, 
taken  in  divided  doses,  was  followed  by  well-marked  improvement  in 
the  digestion  of  fat ;  the  patient  felt  stronger. 

The  few  cases  cited  suggest  that  pancreatic  extracts 
may  be  successfully  used  when  there  is  evidence  that 
digestion  suffers  from  deficiency  of  pancreatic  juice. 
When  the  lesion  is  caused  by  malignant  growth  or  is 
associated  with  diabetes,  though  permanent  benefit  can- 
not result,  it  may  be  possible  to  strengthen  the  patient 
and  retard  emaciation. 

Pancreatic  Infantilism. — Bramwell  '^^  has  described  a 
case  which  he  believes  affords  evidence  that  retarded 
development  in  children  may  be  referable  to  pancreatic 
defect.  A  boy  eighteen  years  old,  who  had  suffered  with 
diarrhoea  during  nine  years,  had  exhibited  arrest  of 
physical  development  after  the  eleventh  year.  Follow- 
ing the  administration  of  glycerin  extract  of  pancreas 
there  was  disappearance  of  diarrhoea  and  rapid  increase 
in  weight.  Thompson  ^^  described  two  similar  cases  with 
diarrhoea;  a  man  of  twenty-four  had  the  appearance  of  a 
boy  of  ten  and  a  boy  of  eighteen  resembled  a  child  of  nine 
years.  Improvement  followed  the  use  of  pancreatic 
extract.  Eentoul  ^^  records  a  similar  condition  occurring 
in  a  girl  with  arrested  development.  Direct  evidence 
of  pancreatic  disease  in  these  cases  is  wanting,  and  there 
is  some  resemblance  to  the  condition  of  infantilism  from 
chronic     intestinal     infection     described     by     Herter.^^ 

"  Bramwell :  Scottish  Med.  and  Surg.  Jour.,  1904,  xiv,  321. 
"  Thompson,  cited  by  Mayo  Robson  and  Cammidge. 
"  Rentoul :  British  Med.  Jour.,  1904,  ii,  1011. 
"  Herter :  Infantilism,  New  York,  1908. 


98  DISEASE  OF  THE  PANCREAS 

Langdon-Brown  ^*  saw  a  boy  with  congenital  syphilis 
sixteen  years  of  age  who  had  the  appearance  of  a  child 
eight  or  ten  yesus  old;  there  was  diarrhoea  with  fatty 
stools.  Pancreatitis  believed  to  be  syphilitic  was  found 
at  autopsy, 

CHANGES    IN   THE    URINE    REFERABLE    TO    PANCREATIC 

DISEASE. 

Numerous  attempts  have  been  made  to  find  in  the 
urine  changes  which  indicate  pancreatic  disease.  The 
conditions  with  which  sugar  in  the  urine  may  be  regarded 
as  an  index  of  pancreatic  disease  will  be  discussed  in  a 
subsequent  chapter. 

Diminution  of  indican  and  of  other  ethereal  sulphates 
has  been  believed  to  give  evidence  that  pancreatic  juice 
fails  to  reach  the  intestine.  Since  products  of  pancre- 
atic digestion  are  more  readily  decomposed  by  bacteria 
than  unchanged  protein  it  has  been  suggested  that  prod- 
ucts of  decomposition  will  reach  the  urine  in  diminished 
quantity  when  the  pancreas  is  diseased.  Gerhardi^* 
found  indican  absent  in  the  urine  of  an  individual  with 
acute  hemorrhagic  pancreatitis  accompanied  by  symp- 
toms of  intestinal  obstruction.  On  the  contrary,  no 
diminution  of  indican  has  been  found  after  removal  of 
the  gland,  and  Northrup  and  Herter  °'^  noted  an  increased 
ratio  of  ethereal  to  preformed  or  neutral  sulphates  in  the 
urine  of  a  patient  with  carcinoma  of  the  pancreas.  Edr 
sail  ^*   thinks  that  diminution  of  ethereal  sulphates  in 

"  Langdon-Brown  :  Practitioner,  1905,  xxii,  233. 
"Gerhardi:  Virehow's  Arch.,  1886,  cvi,  303. 

'■"Northrup  and  Herter:  American  Jour,  of  the  Med.  Scien.,  1899, 
cxvii,  131. 

"  Edsall :  American  Jour,  of  the  Med.  Scien.,  1901,  cxxi,  401. 


THE  PANCREAS  AND  DIGESTION  99 

the  urine  suggests  pancreatic  disease  when  conditions  are 
present  which  usually  cause  their  increase,  but  recognizes 
the  fact  that  they  may  be  diminished  with  other  condi- 
tions which  do  not  affect  the  gland. 

Pentose  has  been  obtained  by  Hammarsten  ^^  from  a 
nucleoprotein  prejDared  from  the  pancreas,  and  although 
the  same  substance  has  subsequently  been  split  from 
nucleoprotein  of  other  organs  it  is  believed  to  be  more 
abundant  in  the  pancreas  than  elsewhere  (Neuberg^^). 
Pentose  was  found  by  Salkowski  and  Jastrowitz  ^^  in  the 
urine  of  a  patient  with  temporary  glycosuria  following 
morphine  poisoning,  and  later  Salkowski  ^^  suggested 
that  the  substance  may  be  formed  from  the  pancreas  and 
indicate  pancreatic  disease.  There  has  been  little  evi- 
dence to  confirm  this  suggestion.  Kiilz  and  Vogel  ^^  ob- 
tained reactions  indicating  the  occurrence  of  pentosuria 
in  sixty-four  of  eighty  patients  with  diabetes,  but  Bial 
and  Blumenthal  ^^  have  failed  to  find  pentosuria  with 
diabetes. 

Cammidge  ^^  has  described  a  reaction  to  be  used  for 
the  diagnosis  of  various  forms  of  pancreatic  disease,  in- 
cluding acute  and  chronic  inflammation  and  carcinoma. 

Cammidge  has  used  at  first  two  reactions  (reaction  A 
and  B)  and  has  found  that  the  precipitate  obtained  with 

°^  Hammarsten :    Zeit.  f .  physiol.  Chem.,  1894,  xix,  19. 

^^Neuberg:  Rev.  d.  deutsch.  chem.  Gesell.,  1902,  Ixxxv,  147. 

**  Salkowski  and  Jastrowitz :  Cent,  f .  med.  Wiss.,  1892,  xxx,  337, 
593. 

'°  Salkowski :  Berliner  kliu.  Woch.,  1895,  xxxii,  364. 

'"  Kiilz  and  Vogel :  Zeit.  f .  Biol.,  1895,  xxxii,  185. 

"  Bial  and  Blumenthal :  Deutsche  med.  Woch.,  1901,  xxvii,  349. 

"*  Cammidge:  Lancet,  1904;  British  Med.  Jour.,  1906,  i,  1150; 
Surg.,  Gynec.  and  Obstet.,  1908,  vi,  22. 


100  DISEASE  OF  THE  PANCREAS 

one  (A)  has  been  greater  than  that  obtained  with  the 
other  (B)  whenever  pancreatic  disease  has  been  present. 
Differences  in  the  character  of  the  precipitate  aid,  he  has 
claimed,  in  distinguishing  acute,  chronic,  and  malignant 
disease  of  the  gland.  He  has  found  that  the  second 
reaction  (B)  is  caused  by  gh^curonic  acid  and  in  a  later 
publication  has  described  a  method  (reaction  C)  in 
which  glycuronic  acid  is  removed  by  basic  lead  acetate. 
The  phenylhydrazine  test  applied  to  urine  previously 
boiled  with  strong  hydrochloric  acid  and  then  treated 
with  basic  lead  acetate  causes  in  cases  of  pancreatic 
disease  the  formation  of  sheaves  of  yellow  crystals  which 
are  soluble  in  dilute  hydrochloric  acid  and  have  a  melting 
point  near  160°  C.  Cammidge  thinks  it  probable  that 
the  reaction  is  dependent  upon  the  presence  of  a  sub- 
stance which  by  hydrolysis  with  strong  acid  yields  a  body 
giving  the  reactions  of  pentose. 

The  reaetion  just  described  has  been  obtained  by  Cammidge  in 
both  of  two  cases  of  acute  pancreatitis,  in  all  of  65  instances  of  chronic 
pancreatitis,  in  4  of  16  cases  of  cancer  of  the  gland ;  it  has  been  absent 
in  all  save  4  cases  without  pancreatitis  and  in  the  urine  of  50  normal 
individuals.  He  has  examined  the  urine  from  4S  diabetics  and  has 
obtained  a  positive  result  in  36  instances  (75  per  cent.)  Eloesser"' 
using  Reactions  A  and  B  has  failed  to  obtain  the  reaction  of  Cammidge 
in  normal  individuals;  it  has  been  present  in  three  cases  of  carcinoma 
of  the  pancreas,  and  in  four  instances  of  chronic  pancreatitis,  and  has 
been  obtained  in  two  instances  of  cholelithiasis  and  in  one  patient  with 
carcinoma  of  the  stomach.  Eichler*"  found  that  the  urine  of  normal 
dogs  failed  to  give  the  reaction  but  obtained  it  after  the  expei-imental 
production  of  acute  pancreatitis  in  three  animals. 


Loe.  cit.,  p.  38. 

Eiehler:  Berliner  klin.  Woch.,  1907,  xliv,  7G9. 


THE  PANCREAS  AND  DIGESTION  101 

Among-  110  cases  which  g-ave  no  e\i(k'nce  of  jjancreatie  disease 
Taylor  "  obtained  a  positive  reaction  in  9  instances.  Watson  °^  studied 
121  eases;  a  pronounced  reaction  occurred  in  12,  of  which  10  exhibited 
symptoms  suggesting  pancreatic  disease,  confirmed  by  operation  or 
autopsy  in  6  cases;  a  moderate  reaction  occurred  in  16  eases,  of  which 
only  six  had  symptoms — e.g.,  glycosuria,  gall-stones — suggesting  dis- 
ease of  the  pancreas,  confirmed  by  autopsy  in  only  one  instance.  A 
slight  reaction  was  obtained  in  18  cases  and  no  reaction  in  75  cases; 
among  these  cases  evidence  of  pancreatic  disease  was  appai-ently 
wanting. 

The  reaction  has  been  obtained  in  a  large  proportion 
of  instances  in  which  pancreatic  disease  has  been  demon- 
strated or  suspected.  Nevertheless,  the  reaction  may 
occur  without  pancreatic  disease  and  is  occasionally  ab- 
sent in  association  with  lesion  of  the  gland.  Peculiari- 
ties of  the  reaction  will  not  serve  to  distinguish  different 
forms  of  pancreatic  disease. 

"'Taylor:  Lancet,  1906,  i,  1818. 

""  Watson :  British  Med.  Jour.,  1908,  i,  858. 


CHAPTER  V. 

THE  PANCREAS  AND  CARBOHYDRATE  METABOLISM. 

Before  considering  the  relationship  of  the  disease 
diabetes  mellitus  to  lesions  of  the  pancreas  it  is  desirable 
to  review  hastily  essential  facts  which  concern  this  dis 
turbance  of  nutrition.  The  literature  of  diabetes  mel- 
litus is  voluminous.  To  the  great  clinical  importance  of 
the  disease  is  added  the  interest  which  attaches  to  its 
bearing  upon  the  physiology  of  carbohydrate  metabol- 
ism. Nevertheless,  observations  which  have  been  fully 
established  are  few,  and  though  the  condition  is  subject 
to  varied  experimentation,  the  results  obtained  have  been 
often  contradictory.  The  physiology  of  carbohydrate 
assimilation  is  not  as  yet  explained,  and  the  disturbances 
which  it  undergoes  are  equally  obscure. 

The  normal  blood,  it  is  well  known,  contains  a  small 
quantity  of  sugar,  which  occurs  as  glucose  or  grape 
sugar,  and  is  almost  constant  in  amount  (0.1  per  cent, 
to  0.2  per  cent.).  A  very  minute  quantity  which  is  nor- 
mally excreted  by  the  kidneys  can  be  demonstrated  in  the 
urine  by  the  use  of  special  methods,  but  is  not  detected  by 
the  tests  for  sugar  ordinarily  employed.  Excretion  of 
an  increased  quantity  of  glucose  is  the  most  conspicuous 
feature  of  diabetes  mellitus,  but  such  glycosuria  is  de- 
pendent upon  underlying  metabolic  disturbances  which 
manifest  themselves  by  a  variety  of  symptoms.  In- 
creased excretion  of  sugar  by  the  urine  can,  however, 
occur  without  diabetes,  and  a  variety  of  causes  produce 

102 


PANCREAS  AND  CARBOHYDRATE  METABOLISM    103 

glycosuria  in  the  absence  of  the  grave  alterations  of 
nutrition  which  characterize  this  disease. 

Carbohydrates  which  are  ingested  with  the  food,  and 
in  very  great  i)art  absorbed  as  glucose,  are  carried  to 
the  liver  by  the  portal  circulation,  and  Von  Mering  ^  has 
shown  by  direct  observation  that  the  quantity  of  sugar 
in  the  portal  blood  is  increased  after  a  meal.  The  liver 
has  the  power  to  store  up  sugar  carried  to  it  by  the 
blood;  Claude  Bernard,  and  later  Schopffer,^  found  that 
sugar  injected  into  the  mesenteric  vein  disappears, 
whereas  an  equal  quantity  injected  into  a  systemic  vein, 
is  not  removed  from  the  blood  and  causes  glycosuria. 

Claude  Bernard  made  the  important  discovery  that 
sugar  carried  to  the  liver  is  stored  in  the  form  of  glyco- 
gen, which,  when  needed,  is  returned  as  glucose  to  the 
blood.  After  ingestion  of  carbohydrates  the  amount 
of  glycogen  in  the  liver  increases,  but  disappears  almost 
completely  after  prolonged  abstinence  from  food.  The 
liver,  however,  is  not  the  only  organ  that  stores  glyco- 
gen ;  it  is  present  in  considerable  quantity  in  the  muscles, 
being  increased  by  the  ingestion  of  carbohydrates  in 
large  amount  and  diminished  by  hunger  or  by  prolonged 
muscular  exertion.  The  muscle  cells  consume  carbohy- 
drates during  activity. 

The  ability  of  the  liver  to  transform  glucose  into 
glycogen  is  limited,  and  if  in  a  healthy  man  or  animal  a 
very  large  amount  of  sugar  is  rapidly  absorbed  from  the 
gastro-intestinal  tract,  the  quantity  of  sugar  in  the  blood 
is  increased,  and  is  consequently  excreted  by  the  urine. 

^  Von  Mering :  Arch,  f ,  Anat.  u.  Physiol.,  1877.     Physiol.  Abt., 
379. 

"  Schoj)£fer :  Arch,  f .  exper.  Path.  u.  Pharm.,  1873,  i,  73. 


lot  DISEASE  OF  THE  PANCREAS 

The  liver,  therefore,  acting  as  a  storehouse  prevents  the 
quantity  of  sugar  in  the  blood  from  rising  above  a  rela- 
tively fixed  amount  (0.1  to  0.2  per  cent.) ;  but  if  within 
a  given  time  the  capacity  of  the  liver  is  exceeded,  sugar 
accumulates  in  the  blood  and  is  thrown  off  by  the  kidneys ; 
alimentary  glycosuria  preceded  by  alimentary  hypergly- 
caemia  follows,  both  being  the  result  of  the  limited  capa- 
city of  the  liver  and  certain  other  organs  to  store  sugar 
absorbed  from  the  food.  This  limit  varies  in  different 
individuals  and  is  diminished  under  certain  pathological 
conditions. 

A  normal  individual  is  able  to  assimilate  from  one 
hundred  and  fifty  to  two  hundred  and  fifty  grammes 
of  glucose  taken  after  fasting,  and  no  sugar  appears  in 
the  urine.  Under  certain  conditions,  notably  in  many 
cases  of  exophthalmic  goitre  and  with  certain  neuroses, 
glycosuria  follows  the  ingestion  of  much  smaller  quanti- 
ties. Diseased  conditions  of  the  liver  might  be  expected 
to  favor  the  occurrence  of  this  form  of  glycosuria,  and 
in  some  cases  of  cirrhosis  alimentary  glycosuria  is  read- 
ily produced,  but  the  result  of  such  investigations  have 
been  by  no  means  constant.  Minkowski  ^  has  shown 
that  alimentary  glycosuria  may  occur  in  dogs  after  par- 
tial extirpation  of  the  pancreas,  and  Wille^  and  G. 
Hoppe-Seyler  ^  have  demonstrated  its  association  with 
certain  lesions  of  the  human  gland. 

Temporary  glycosuria  follows  a  variety  of  injuries  to 
the  nervous  system;  the  so-called  diabetic  puncture  of 
Claude  Bernard  is  the  best-known  illustration.    Destruc- 

'  Minkowski:  Arch.  f.  exper.  Path.  u.  Pharm.,  1893,  xxxi,  85. 
*  Wille :  Deutsehes  Arch.  f.  klin.  Med.,  1899,  Ixiii,  546. 
'Hoppe-Seyler,  G. :  Ihid.,  1904,  Ixxxi,  119. 


PANCREAS  AND  CARBOHYDRATE  METABOLISM  105 

tion  of  the  gray  matter  in  the  floor  of  the  fourth  ven- 
tricle, a  few  millimetres  above  the  point  of  the  calamus 
scriptorius,  in  rabbits,  dogs,  birds,  and  frogs,  is  fol- 
lowed by  glycosuria.  In  rabbits,  within  one  to  three 
hours  after  this  operation,  sugar  appears  in  the  urine, 
and  may  constitute  as  much  as  6  per  cent. ;  excretion  of 
sugar  continues  only  five  or  six  hours.  The  condition  is 
associated  with  an  increase  of  the  sugar  in  the  blood, 
and  a  variety  of  experiments  indicate  that  the  puncture 
causes  a  discharge  of  glycogen  from  the  liver  and  prob- 
ably from  the  muscles  and  other  organs  into  the  blood, 
but  the  evidence  upon  this  point  is  in  part  conflicting. 
In  animals  deprived  of  glycogen  by  prolonged  hunger 
the  puncture  is  ineffectual,  while  after  section  of  all 
nerves  to  the  liver  glycosuria  is  trivial. 

A  variety  of  other  operations  upon  the  nervous  sys- 
tem have  been  followed  by  temporary  glycosuria  pre- 
sumably analogous  with  that  of  C.  Bernard's  puncture; 
glycosuria,  for  example,  has  been  observed  after  extir- 
pation of  the  superior  cervical  ganglion,  after  section 
and  stimulation  of  the  spinal  cord  at  the  level  of  the 
brachial  plexus,  after  stimulation  of  the  central  stump 
of  the  vagus  when  cut,  and  after  section  of  the  sciatic 
nerve  and  stimulation  of  its  central  end. 

One  form  of  glycosuria  which  has  been  the  subject 
of  varied  experimentation  is  unaccompanied  by  an  in- 
crease of  sugar  in  the  blood.  Following  the  administra- 
tion by  feeding  or  injection  of  the  glucoside  phlorhizin, 
glycosuria  occurs  in  man  and  in  lower  animals  and  per- 
sists often  twenty-four  hours  or  longer,  the  amount  of 
sugar  excreted  greatly  exceeding  that  contained  in  the 
glucoside.     The  quantity  of  sugar  in  the  blood  does  not 


106  DISEASE  OF  THE  PANCREAS 

increase,  even  though  excretion  of  sugar  be  prevented 
by  extirpation  of  the  kidneys  or  ligation  of  the  ureters. 
Hence  it  is  believed  that  the  poison  produces  some  change 
as  the  result  of  which  the  kidneys  are  no  longer  able  to 
hold  back  the  sugar  normally  present  in  the  blood.  Min- 
kowski has  suggested  that  the  glucoside  phlorhizin  is  split 
by  the  kidney  into  a  substance,  phloretin,  and  a  sugar 
closely  resembling  glucose;  the  latter  is  excreted,  but 
phloretin  is  retained  and  unites  with  more  glucose,  which 
in  turn  is  separated  by  the  kidneys. 

Asphyxiation,  poisoning  with  carbon  monoxide,  mor- 
phine, curare,  and  a  variety  of  substances,  cause  glyco- 
suria the  pathogenesis  of  which  is  not  understood.  Note 
worthy  in  this  connection  is  the  experimental  glycosuria 
produced  by  lierter  and  Richards  with  adrenalin  chlo- 
ride, potassium  cyanide  and  a  variety  of  other  reducing 
substances  (see  p.  116).  In  all  such  instances  the  condi- 
tion is  temporary  and  thus  distinguishable  from  the  per- 
manent glycosuria  which  in  man  is  associated  with  the 
constitutional  disease  diabetes  mellitus. 

Permanent  glycosuria  accompanied  by  sjniiptoms 
comparable  to  those  occurring  in  human  diabetes  can 
be  produced  by  but  one  experimental  means.  The  in- 
vestigations of  Von  Mering  and  Minkowski  ^  stand  in  im- 
portance next  to  those  of  Claude  Bernard.  They  have 
demonstrated  that  the  organ  is  essential  to  normal 
carbohydrate  metabolism  and  its  extirpation  is  followed 
by  a  condition  which  reproduces  in  animals  diabetes 
mellitus. 

'Von  Mering  and  Minkowski:  Arch.  f.  exper.  Path.  u.   Pharm., 
1890,  xxvi,  371. 


PANCREAS  AND  CARBOHYDRATE  METABOLISM  107 

Extirpation  of  the  Pancreas. — Observations  of  Von 
Mering  and  Minkowski,  later  amplified  by  Minkowski, 
have  shown  that  complete  removal  of  the  pancreas  in 
dogs  is  followed  within  twenty-four  hours  by  the  appear- 
ance of  sugar  in  the  urine.  The  quantity  of  sugar  grad- 
ually increases,  and  usually  reaches  a  maximum  on  the 
third  day,  when  it  may  form  from  8  to  10  per  cent.,  even 
though  no  carbohydrates  have  been  taken  into  the  gastro- 
intestinal tract.  Glycosuria  continues  and  is  associated 
with  a  corresponding  hyperglycsemia.  Sugar  accumu- 
lates in  the  blood  where  it  may  constitute  as  much  as  0.5 
per  cent. ;  sugar  present  in  excess  in  the  blood  is  ex- 
creted by  the  kidneys.  Glycogen  disappears  almost  com- 
pletely from  the  liver  and  other  organs. 

Symptoms  analogous  to  those  of  human  diabetes 
occur,  and  there  is  greatly  increased  appetite  and  ex- 
cessive thirst,  accompanied  by  increase  in  the  amount 
of  urine;  gradual  emaciation  and  progressive  weakness 
precede  death,  which  occurs  several  weeks  after  the  oper- 
ation. Acetone  and  diacetic  and  oxybutyric  acid  have 
been  found  in  the  urine.  Minkowski  observed  that  grape 
sugar  taken  with  the  food  is  completely  excreted  by  the 
urine.  Moreover,  since  glycosuria  continues  even  when 
the  diet  is  entirely  free  from  carbohydrates,  sugar  is 
doubtless  formed  within  the  body;  the  amount  bears  a 
constant  ratio  (2.8:1)  to  the  quantity  of  nitrogen 
eliminated.  This  constant  ratio  is  best  explained  by 
supposing  that  the  total  quantity  of  sugar  formed  in 
the  body  from  protein,  after  removal  of  the  pancreas, 
is  excreted  by  the  kidneys.  Immediately  before  the 
fatal  termination  of  the  disease,  when  emaciation  and 
weakness  are  extreme,  and  particularly  with  the  onset 


108  DISEASE  OF  THE  PANCREAS 

of  complications, — for  example,  suppurative  peritonitis 
as  a  consequence  of  the  operation, — sugar  may  disap- 
pear from  the  urine.  A  similar  phenomenon  is  observed 
in  human  diabetes,  and  is  probably  due  to  some  inter- 
ference with  the  absorption  of  sugar  or  with  its  produc- 
tion within  the  body  from  proteins. 

Partial  removal  of  the  pancreas — if  a  considerable 
part,  a  fourth  or  a  fifth  (in  the  dog),  remains — is  not 
followed  by  diabetes;  but  a  smaller  part — for  example, 
an  eighth  or  a  twelfth — does  not  suffice  to  prevent  its 
onset.  In  such  case  the  severity  of  the  disease  is  varia- 
ble, and  disturbed  metabolism  may  be  indicated  only  by 
an  intolerance  of  the  organism  for  sugar,  a  very  small 
quantity  taken  as  food  causing  glycosuria.  This  alimen- 
tary glycosuria  may  therefore  indicate  partial  insuffi- 
ciency of  the  pancreas. 

Experiments,  with  negative  results,  have  been  under- 
taken to  show  that  injury  to  the  organs  surrounding  the 
pancreas,  particularly  to  the  nerves  and  ganglia,  is  re- 
sponsible for  the  resulting  disturbances  of  metabolism. 
Slight  injury  to  the  pancreas  not  infrequently  causes 
transient  glycosuria,  but  never  diabetes.  That  the  dis- 
ease is  not  caused  by  inhibition  of  the  pancreatic  secre- 
tion or  by  its  removal  from  the  intestine  is  shown  by 
the  absence  of  glycosuria  after  ligation  of  the  pancreatic 
duct  or  after  the  formation  of  a  pancreatic  fistula ;  though 
the  pancreatic  juice  fails  to  reach  the  intestine  diabetes 
does  not  result. 

An  exception  to  the  foregoing  statements  is  perhaps 
the  observation  of  E.  Pfliiger  "^  who  has  claimed  that  re- 

'Pfliiger,  E.:  Pfliiger's  Arch.,  1907,  exviii,  267;  exix,  227;  297. 


PANCREAS  AND  CARBOHYDRATE  METABOLISM  109 

moval  of  the  duodenum  or  destruction  of  its  nervous 
connection  with  the  pancreas  is  followed  by  fatal  dia- 
betes. Ehermann^  has  shown  that  such  operations  in 
warm-blooded  animals  are  not  followed  by  diabetes. 

The  observations  of  Von  Mering  and  Minkowski  on 
dogs  have  been  confirmed  by  a  very  large  number  of 
experiments,  and  extended  observations  indicate  that 
they  are  applicable  to  all  classes  of  vertebrates.  In  rare 
instances  discordant  results  have  been  obtained,  but  have 
doubtless  been  due  to  the  mechanical  difficulty  of  com- 
pletely removing  the  gland.  Diabetes  has  been  pro- 
duced in  cats  and  in  pigs  by  Minkowski.  Both  Wein- 
traud  ^  and  Kausch  ^^  have  removed  the  gland  from 
various  birds, — namely,  ducks,  geese,  falcons,  buzzards, 
and  ravens, — and  have  noted  glycosuria  persisting  until 
death.  Of  considerable  interest,  however,  is  the  observa- 
tion of  Kausch  that  in  geese  and  ducks  the  lesion  is  not 
constantly  followed  by  glycosuria,  although  the  quantity 
of  sugar  in  the  blood  is  increased  as  in  other  species; 
it  appears  that  sugar  is  not  readily  excreted  by  the  kid- 
neys of  these  animals.  Glycosuria  with  fatal  termina- 
tion has  been  shown  to  follow  the  operation  in  frogs  and 
turtles   (Aldehoff  ^^),  and  in  ells   (Capparelli  ^2). 

The  results  of  experimental  studies  just  cited  are 
applicable  to  man.  Pranke  ^^  found  the  head  of  the  pan- 
creas in  a  woman  sixty-six  years  of  age  invaded  by  malig- 
nant growth  and  with  much  difficulty  removed,  he  be- 

'Ehermann:  Ibid.^  1907,  cxix,  295. 

°  Weintraud :  Arch,  f .  exper.  Path.  u.  Pharm.,  1894,  xxxiv,  303. 

'"Kausch:  Ibid.,  1896,  xxxvii,  274. 

"  Aldehoff:  Zeit.  f.  Biol,  1891,  xxviii,  293. 

"^  Capparelli :    Arch.  ital.  de  biol.,  1894,  xxi,  398. 

"Franke:  Arch.  f.  klm.  Chir.,  1901,  Ixiv,  364. 


110  DISEASE  OF  THE  PANCREAS 

lieved,  the  entire  gland.  Sugar  appeared  in  the  urine 
eighteen  days  later,  the  amount  reaching  3  per  cent.; 
death  occurred  after  six  months.  Zweifel  ^^  recorded  the 
removal  of  a  pancreatic  cyst  together  with  the  splenic 
part  of  the  gland  six  centimetres  in  length;  the  part 
remaining  was  three  centimetres  in  length.  On  the 
tenth  day  after  operation  sugar  appeared  in  the  urine, 
persisted  three  days  and  disappeared  although  the  diet 
was  unchanged;  sugar  reappeared  on  the  fifteenth  day 
and  again  on  the  twenty-first  day,  but  was  absent  two 
months  after  operation.  Hahn^^  states  that  he  has 
found  sugar  in  the  urine  after  removal  of  a  small  piece 
of  the  pancreas. 

The  following  case  for  which  I  am  indebted  to  the 
kindness  of  Dr.  David  Marine,  who  performed  the 
autopsy,  shows  that  as  much  as  one-third  of  the  pancreas 
may  be  insufiicient  to  prevent  the  onset  of  glycosuria. 

A  well-developed,  well-nourished  woman,  forty-seven  years  of  age, 
had  complained  of  pain  referred  to  the  inner  side  of  the  thighs  and 
mone  severe  on  the  left  side.  The  urine  had  contained  red  blood- 
corpuscles  and  pus  cells  and  catheterization  of  the  ureters  showed  that 
these  cells  were  from  the  left  kidney.  Examination  of  the  abdomen 
showed  only  slight  tenderness.  An  incision  into  the  abdominal  cavity 
was  made  through  the  median  line  and  the  appendix  which  was  bound 
by  adhesions  was  removed.  The  uterus  which  was  retroflexed  was  sus- 
pended from  the  abdominal  wall.  On  the  left  side  could  be  felt  what 
was  thouglit  to  be  a  sclerotic  and  atrophic  kidney  with  a  stone  in  its 
pelvis;  the  right  kidney,  the  gall-bladder,  the  stomach  and  the  pancreas 
were  felt,  it  was  thought,  and  appeared  normal.  The  left  kidney 
was  sought  through  an  oblique  incision  in  the  back  and  the  peritoneal 

"Zweifel:  Cent.  f.  Gynsec,  1894,  xviii,  641. 

"  Hahn :  Cent,  f .  Chir.,  1894,  xxi,  Beilage  zu  No.  30,  57. 


PANCREAS  AND  CARBOHYDRATE  METABOLISM  111 

cavity  was  entered.  A  part  of  the  pancreas  mistaken  for  an  atrophic 
kidney  was  removed;  there  was  considerable  hemorrhage,  and  the 
wound  was  packed  with  gauze.  Examination  showed  that  the  pancreatic 
tissue  removed  was  normal  and  constituted  two-thirds  of  the  gland. 
Several  houre  after  operation  the  pulse  became  rapid  (156  per  minute) 
and  there  was  considerable  pain,  nausea  and  vomiting.  On  the  follow- 
ing day  there  was  violent  paroxysmal  epigastric  pain  uncontrolled 
by  morphia.  Vomiting  ceased  and  pain  became  less.  There  was  de- 
lirium and  elevation  of  temperature  (102.8°  F.).  The  temperature  rose 
further  (104.4°  F.)  and  death  occurred  three  days  after  operation. 

Urine  before  operation,  sp.  gT.  1010,  contained  no  sugar  and  a 
trace  of  albumin.  Eight  hours  after  operation  there  was  slight  reduc- 
tion of  Fehling-'s  solution  and  a  moderate  amount  of  albumin.  One 
day  after  operation  (sp.  gr.  1015  to  1021)  there  was  slight  reduction 
and  a  trace  of  albumin;  two  days  after  operation  there  was  moderate 
reduction  of  Fehling's  solution  and  the  polariscope  indicated  an  increase 
of  sugar  during  the  day  from  0.3  to  0.7  per  cent. ;  three  days  after 
operation  (sp,  gr.  1020  to  1021)  there  was  moderate  reduction,  and  on 
two  examinations  0.6  and  1.4  per  cent,  of  sugar. 

Partial  autopsy  has  been  made  through  the  abdominal  incision. 
The  peritoneal  cavity  contams  bloody,  slightly  fetid  fluid.  The  omen- 
tmn  is  attached  to  the  wound  of  the  pancreas  and  in  immediate  contact 
with  the  gland  contains  minute  yeUowish-white  foci  of  fat  necrosis. 
The  splenic  part  of  the  pancreas  has  been  removed  and  the  tissue  in  the 
wound  is  discolored,  soft,  and  cheesy.  The  duodenal  end  of  the  pan- 
creas measures  about  5.5  em.  in  length  and  has  formed  one-third  of 
the  whole  gland;  the  ducts  are  intact. 

The  left  kidney  is  converted  into  a  thin-walled  sac  and  the  im- 
mensely distended  pelvis  contains  opaque  fluid.  Blocking  the  pelvic 
end  of  the  ureter  is  a  calculus  measuring  0.5  by  1  em. 

Anatomical  Diagnosis. — Left  hydronephrosis  with  renal  calculus 
blocking  the  pelvic  end  of  the  ureter;  wound  of  pancreas  and  absence 
of  two-thirds  of  the  gland;  beginning  peritonitis;  acute  splenic  tumor. 

IIow  Does  the  Pancreas  Influence  Carbohydrate 
Metaholismf — The  pancreas  of  vertebrates  is  essential  to 


112  DISEASE  OF  THE  PANCREAS 

carbohydrate  metabolism,  and  removal  or  destruction  is 
followed  by  the  accumulation  of  sugar  in  the  blood  and 
its  excretion  by  the  kidneys.  How  does  the  pancreas  in- 
fluence metabolism!  Abundant  observation  has  demon- 
strated that  injury  to  the  nerves  of  the  pancreas  is  not 
responsible  and  failure  of  the  pancreatic  juice  to  reach 
the  intestine  is  not  its  cause,  for  ligation  of  ducts  is  not 
followed  by  diabetes.  Furthermore,  after  partial  re- 
moval of  the  gland  its  splenic  extremity,  alone  remain- 
ing, may  be  transplanted  into  the  subcutaneous  tissue 
without  complete  destruction  of  its  vascular  connections ; 
the  nerves  of  the  resected  part  are  severed  and  the  pan- 
creatic juice  is  wholly  lost,  yet  glycosuria  does  not  fol- 
low. If  now  the  transplanted  part  be  removed,  diabetes 
ensues. 

The  pancreas  may  influence  carbohydrate  metabolism 
in  one  of  two  ways:  the  organ  may  furnish  something 
essential  to  normal  nutrition,  an  internal  secretion  (to 
be  distinguished  from  the  pancreatic  juice,  the  external 
secretion),  or  the  gland  may  destroy  some  product  which 
accumulates  in  the  body  and  hinders  normal  assimilation 
of  sugar. 

Lepine  ^"  has  believed  that  he  is  able  to  demon- 
strate in  the  blood  a  glycolytic  enzyme  capable  of  trans- 
forming sugar  and  destroyed  by  a  temperature  of  54°  C. 
He  claims  that  it  is  present  in  normal  blood,  but  absent 
in  that  of  lower  animals  deprived  of  the  pancreas  or  in 
human  beings  suffering  with  diabetes.  This  enzyme,  he 
thinks,  is  formed  in  the  pancreas,  from  which  it  is  car- 
ried by  the  lymph  or  blood  to  the  tissues  and  there 


Lepine :  Rev.  de  med.,  1894,  xiv,  Oct.  10. 


PANCREAS  AND  CARBOHYDRATE  METABOLISM  113 

furthers  carbohydrate  assimilation.  The  basis  of  Le- 
pine's  theory  is  the  observation  of  Claude  Bernard  that 
sugar  disappears  from  drawn  blood ;  Lepine  believes  that 
this  glycolysis  is  diminished  in  diabetic  patients  and  in 
dogs  from  which  the  pancreas  is  removed.  Almost  all 
observers  who  have  repeated  his  experiments  have  ob- 
tained negative  results.  The  success  of  thyroid  therapy 
in  the  treatment  of  diseases  presumably  due  to  the 
absence  of  an  internal  secretion  produced  by  the  thyroid 
gland  has  pointed  the  way  to  numerous  analogous  ex- 
periments upon  animals  with  diabetes,  but  glycosuria  has 
not  been  prevented  nor  diminished  by  the  administration 
of  products  obtained  from  the  pancreas. 

Extracts  prepared  from  the  pancreas  do  not  decom- 
pose glucose,  and  evidence  that  the  pancreas  furnishes 
a  glycolytic  enzyme  to  the  blood  is  lacking.  Neverthe- 
less, the  gland  may  furnish  some  substance  which  in- 
creases glycolysis  in  other  organs.  Rahel  Hirsch^^ 
found  that  extract  of  liver  caused  slight  glycolysis 
whereas  addition  of  pancreas  was  followed  by  noteworthy 
increase  of  glycolytic  action. 

Studies  of  Otto  Cohnheim  ^^  have  suggested  an  hy- 
pothesis to  explain  the  relation  of  the  pancreas  to  the 
metabolism  of  sugar.  It  is  well  known  that  the  muscles 
are  capable  of  assimilating  and  destroying  sugar,  yet 
extracts  prepared  from  muscles  have  slight  or  no  glyco- 
lytic activity;  but,  whereas  juice  expressed  from  muscle 
causes  little  decomposition  of  glucose  and  the  juice  ex- 
pressed from  pancreas  does  not  cause  glycolysis,  a  mix- 

"  Hirsch :  Hofmeister's  Beit.,  1903,  iv,  535. 

''  Cohnheim,  0. :  Zeitsch.  f .  physiol.  Chem.,  1903,  xxxix,  336 ;  1904, 
xlii,  401 ;  1905,  xliii,  547 ;  1906,  xlvii,  253. 
8 


114  DISEASE  OF  THE  PANCREAS 

ture  of  juice  from  the  two  organs,  according  to  Cohn- 
heim,  has  the  power  to  break  down  sugar,  so  that  it  is  no 
longer  recognizable  by  its  reducing  action.  Glycolysis 
is  accomplished  by  neither  organ  acting  by  itself,  but  the 
two  in  combination  are  effective.  The  muscle,  Cohnheim 
finds,  contains  a  labile  enzyme,  extraction  of  which  re- 
quires considerable  care.  The  activating  substance  of 
the  pancreas  does  not  possess  the  properties  of  an 
enzyme  and  is  not  destroyed  by  heat.  It  is  soluble  in 
water  and  in  alcohol  and  may  be  preserved  as  an  alcoholic 
extract.  Cohnheim  suggests  that  there  is  .an  analogy 
between  enzyme  of  muscle  and  activator  of  pancreas  on 
the  one  hand,  and  complement  and  amboceptor  on  the 
other;  the  analogy  is  strengthened  by  the  observation 
that  increase  of  pancreatic  activator  above  a  certain 
optimum  may  diminish  glycolysis  caused  by  a  given 
quantity  of  enzyme. 

Claus  and  Embden  ^^  have  failed  to  confirm  the  obser- 
vations of  Cohnheim,  and  attribute  to  bacterial  contami- 
nation the  glycolysis  which  he  has  found.  Cohnheim  has 
maintained  that  action  of  bacteria  has  been  excluded. 
Hall,^^  confirming  the  work  of  Cohnheim,  found  that 
extracts  of  pancreas  and  muscle  in  combination  destroyed 
glucose,  but  failed  to  decompose  levulose.  The  complex- 
ity of  the  subject  is  increased  by  the  claim  of  Stocklasa  ^^ 
that  all  organs,  including  the  pancreas,  contain  glycolytic 
enzyme;  numerous  observers  have  failed  to  confirm  his 


"  Claus  and  Embden :  Hofmeister's  Beit.,  1905,  vi,  214,  343. 
'"  Hall :  American  Journal  of  Physiol.,  1907,  xviii,  283. 
^  Stocklasa:  Chem.  Bench.,  1903,  xxxvi,  622,  4058;  1905,  xxxviii, 
664. 


PANCREAS  AND  CARBOHYDRATE  METABOLISM  115 

opinion.  De  Meyer  ^^  has  fonnd  a  pancreatic  activator, 
but  lias  maintained  that  glycolytic  enzyme  is  formed,  not 
in  the  muscle,  but  in  the  leucocytes. 

Since  sugar  is  excreted  in  the  urine  after  removal  of 
the  pancreas,  even  though  carbohydrates  are  not  taken 
with  the  food,  it  is  evident  that  glucose  can  be  formed 
within  the  body.  Since  the  amount  of  sugar  in  the  urine 
bears  a  constant  ratio  to  the  nitrogen  excreted,  there  can 
be  little  doubt  that  sugar  is  formed  from  proteins,  and 
that  the  entire  amount  of  sugar  thus  formed  is  unas- 
similated  and  excreted.  An  additional  fact  of  consider- 
able interest  is  the  disappearance  of  glycogen  from  the 
liver  and  muscles  after  extirpation  of  the  pancreas.  Ee- 
moval  of  the  gland  renders  the  tissues  unable  to  take 
up  and  assimilate  sugar. 

This  inability  of  the  liver  to  transform  sugar  into 
glycogen  applies  to  glucose,  but  not  to  the  isomeric 
levorotatory  sugar  levulose,  for  after  ingestion  of  the 
latter  glycogen  is  found  in  the  liver.  Schmiedeberg  has 
suggested  that  in  diabetes  glucose  in  the  blood  is  com- 
bined with  some  substance  which  prevents  its  assimilation 
by  the  tissues.  The  tissues  are  nevertheless  able  to  take 
up  the  molecule  of  levulose.  A  somewhat  analogous  ex- 
planation of  phlorhizin  diabetes  advanced  by  Minkowski 
has  already  been  mentioned. 

Effect  of  Adrenal  and  Thyroid  Gland  upon  the  Me- 
tabolic Function  of  the  Pancreas.— The  occurrence  of 
diabetes  mellitus  in  association  with  exophthalmic  goitre 
has  suggested  a  relationship  between  the  thyroid  gland 
and  the  pancreas.     The  production  of  glycosuria  by  ad- 

''De  Meyer:  Ann.  de  I'lnst.  Pasteur,  1908,  xxii,  778.     . 


116  DISEASE  OF  THE  PANCREAS 

ministration  of  adrenalin  has  suggested  that  the  adrenal 
glands  may  influence  carbohydrate  metabolism.  Experi- 
mental data  concerning  the  relationship  of  these  three 
organs  are  difficult  to  interpret. 

By  injecting  extracts  made  from  the  adrenal  gland 
into  the  subcutaneous  tissue  or  into  veins  Blum  ^^  has 
produced  temporary  glycosuria.  Herter  and  Richards  ^^ 
have  found  that  adrenalin  chloride  causes  more  marked 
glycosuria  when  injected  into  the  peritoneal  cavity  than 
when  administered  by  other  methods;  10  per  cent,  of 
sugar  may  be  present  in  the  urine,  and  glycosuria  usually 
continues  during  twenty-four  hours.  By  merely  painting 
the  surface  of  the  pancreas  with  the  extract  a  similar 
effect  is  produced.  Adrenalin,  according  to  Zuelzer  ^^ 
and  Metzger,^*'  causes  hyperglycaemia,  and  excess  of  sugar 
in  the  blood  is  followed  by  glycosuria. 

In  animals  deprived  of  the  thyroid  gland  Eppinger, 
Falta  and  Rudinger  ^'  have  found  that  adrenalin  fails 
to  cause  glycosuria,  but  if  such  animals  are  treated  with 
thyroid  extract  or  with  idothyroin,  adrenalin  has  the 
usual  effect.  Zuelzer  ^^  on  the  one  hand  has  failed  to 
obtain  glycosuria  with  adrenalin  if  pancreatic  tissue  has 
been  simultaneously  administered;  on  the  other  hand, 
Eppinger,  Falta  and  Rudinger  claim  that  the  administra- 
tion of  adrenalin  to  animals  derived  of  the  pancreas 
increases  the  excretion  of  sugar. 

"Blum:  Deutsches  Arch.  f.  klin.  Med.,  1901,  Ixxi,  146. 

'*  Herter  and  Richards:  Med.  News,  1002,  Ixxx,  201. 

"Zuelzer:  Berliner  klin.  Woeh.,  1901,  xxxviii,  1209. 

'"INIetzger:  Miinchen  med.  Woeh.,  1902,  xlix,  478. 

"  Eppinger,  Falta  and  Rudinger :  Zeit.  f .  klin.  Med.,  1908,  Ixvi,  1. 

** Zuelzer:  Verhandl.  d.  24  Kong.  f.  inn.  Med.,  1907,  258. 


PANCREAS  AND  CARBOHYDRATE  METABOLISM  117 

Although  adrenalin  has  no  effect  upon  the  pupil  of 
normal  animals  it  causes  mydriasis,  Loewi  ^^  has  shown, 
in  animals  deprived  of  the  pancreas ;  this  phenomenon  is 
doubtless  produced  by  action  upon  the  sympathetic  ner- 
vous system.  Eppinger,  Falta  and  Rudinger  have  found 
similar  contraction  of  the  pupil  after  injection  of  thyroid 
extract  into  normal  dogs. 

By  ingenious  speculations  Eppinger,  Falta  and  Ru- 
dinger have  attempted  to  explain  the  phenomena  which 
have  been  mentioned,  and  to  define  the  relationship  of  the 
pancreas,  adrenal,  and  thyroid  gland.  Internal  secre- 
tion furnished  by  the  thyroid  stimulates,  they  suggest, 
the  activity  of  the  adrenal,  and  the  secretion  of  the  adre- 
nal stimulates  the  thyroid ;  both  organs  inhibit  the  action 
of  the  pancreas  so  that  with  the  increased  activity  of 
either  the  pancreas  exhibits  diminished  ability  to  control 
the  assimilation  of  sugar.  Administration  of  adrenalin 
to  a  normal  animal,  according  to  this  hypothesis,  in- 
creases the  inhibition  of  the  pancreas  and  glyco- 
suria results,  but  if  adrenalin  is  given  on  the  one 
hand  to  an  animal  which  has  been  deprived  of  its  thyroid 
gland,  or  on  the  other  hand,  to  an  animal  which  receives 
at  the  same  time  pancreatic  tissue  (Zuelzer)  there  is  no 
glycosuria.  Internal  secretion  of  the  pancreas  inhibits 
the  excitability  of  the  sympathetic  nervous  system, 
according  to  Eppinger,  Falta  and  Rudinger,  and  secre- 
tion of  the  adrenal  and  of  the  thyroid  increases  its  excita- 
bility. In  consequence  of  heightened  excitability  follow- 
ing removal  of  the  pancreas  adrenalin  causes  contraction 
of  the  pupil. 

'"  Loewi :  Arch,  f .  exper.  Path.  u.  Phann.,  1908,  lix,  83. 


CHAPTER  VI. 

HEMORRHAGIC    NECROSIS    OF    THE    PANCREAS    (aCUTE 
HEMORRHAGIC    PANCREATITIS). 

Acute  inflammation  of  the  pancreas  has  attracted 
much  attention,  yet  the  nature  and  the  cause  of  the  lesions 
which  accompany  it  have  been  obscure.  While  suppura- 
tive inflammation  resembles  abscess  in  other  organs,  so- 
called  hemorrhagic  and  gangrenous  pancreatitis  finds 
little  analogy  in  the  liver,  spleen,  kidneys,  or  indeed  in 
the  salivary  glands,  which  resemble  in  many  respects 
the  pancreas.  The  difficulty  of  deciding  what  shall  be 
regarded  an  inflammatory  process  is  here  encountered; 
distinctions  between  hemorrhagic  pancreatitis  and 
hemorrhage  into  the  organ,  though  usually  emphasized 
in  writings  upon  diseases  of  the  gland,  are  not  clearlj^ 
drawn. 

Varieties  of  Acute  Pancreatitis. — A  well-defined 
classification  of  acute  lesions  of  the  gland  was  intro- 
duced by  Fitz,^  and  was  based  upon  an  analysis  of  cases 
studied  by  himself,  as  well  as  of  those  recorded  in  the 
literature.  So-called  hemorrhagic  pancreatitis,  had 
already  been  observed  by  Rokitansky  ^  and  by  Klebs.^ 
Both  Friedreich  *  and  Fitz  recognized  pancreatic  hemor-, 
rhage  as  an  independent  condition, — a  lesion  unaccom- 
panied by  inflammatory  changes.     Fitz  found  that  acute 


'  Fitz :   Acute  Pancreatitis.  Med.  Record,  1889,  xxxv,  197,  225,  253. 
^  Rokitansky :    Lehrbuch   der  path.  Anat.,  Vienna,  1863,  iii,  313. 
'Klebs:    Handbuch  d.  path.  Anat.,  Berlin,  1869,  i,  271. 
*  Loc.  cit.,  p.  V. 
118 


HEMORRHAGIC  NECROSIS  OF  PANCREAS  119 

inflammatory  alterations  of  the  pancreas  fell  into  three 
groups  which,  to  emphasize  their  conspicuous  feature, 
he  designated  hemorrhagic,  gangrenous,  and  suppura- 
tive pancreatitis. 

Hemorrhagic  pancreatitis,  described  by  Fitz,  occurs 
most  frequently  in  those  who  have  had  previous  attacks 
of  ''gastric  or  gastroduodenal  dyspepsia."  It  begins 
with  intense  pain  in  the  upper  abdomen,  followed  by 
vomiting  and  not  infrequently  by  slight  swelling  of  the 
epigastrium,  associated  with  tenderness  and  accompa- 
nied by  obstinate  constipation.  The  temperature  is  nor- 
mal or  subnormal,  and  symptoms  of  collapse  precede 
death,  which  usually  occurs  between  the  se^cond  and 
fourth  days.  The  pancreas  is  found  to  be  enlarged,  and 
its  interstitial  tissue,  as  well  as  the  tissues  in  its  neighbor- 
hood, is  infiltrated  with  blood.  Microscopic  examination 
shows  the  presence  of  cellular  and  fibrinous  exudates 
together  with  necrosis  of  the  parenchyma.  In  the  fat  of 
the  omentum  and  of  the  subperitoneal  tissue  are  the  dis- 
seminated foci  of  necrosis  to  which  Balser  has  directed 
attention. 

Gangrenous  pancreatitis,  according  to  Fitz,  though 
it  may  follow  other  conditions,  is  usually  the  result  of 
hemorrhagic  i^ancreatitis,  and  in  at  least  half  of  the 
recorded  cases  evidence  of  previous  hemorrhage  is 
present  in  the  altered  gland.  The  clinical  symptoms  of 
the  two  conditions  resemble  one  another  closely,  but 
where  the  pancreas  is  found  to  be  gangrenous  the  illness 
has  been  of  longer  duration,  proving  fatal  at  the  end 
of  several  weeks.  The  organ  is  enlarged,  often  soft  and 
friable,  and  of  a  color  which  varies  from  mottled  red  and 
gray  to  dark  brown  or  black;  by  extension  of  the  gan- 


120  DISEASE  OF  THE  PANCREAS 

grenous  process  to  the  tissues  about  the  organ  almost 
complete  sequestration  may  result.  Since  the  gangren- 
ous pancreas  lies  in  the  posterior  wall  of  the  lesser  peri- 
toneal cavity,  peritonitis  ensues,  and  this  cavity  is  con- 
verted into  an  abscess  containing  pus  and  necrotic 
material.  In  some  cases  the  completely  sequestrated 
pancreas,  attached  by  only  a  few  shreds  of  tissue,  is 
surrounded  by  purulent  fluid.  Communication  may  be 
formed  with  the  intestine,  and  in  two  cases  described 
by  Ohiari  ^  a  large  mass  of  necrotic  material  discharged 
by  the  rectum  was  recognized  to  be  gangrenous  pan- 
creatic tissue.  Disseminated  fat  necrosis,  to  be  de- 
scribed later,  accompanies  the  gangrenous  lesion. 

Suppurative  pancreatitis,  described  by  Fitz,  resembles 
suppurative  inflammation  of  other  organs ;  the  gland  may 
contain  abscess  cavities  of  various  sizes,  the  organ  is 
enlarged  and  the  periiDancreatic  tissue  is  indurated. 
Suppurative  inflammation  rarely  pursues  an  acute 
course,  but  persists  for  weeks  or  months,  and  abscess 
cavities  may  discharge  into  the  stomach  or  duodenum, 
or,  rupturing  into  the  lesser  peritoneal  cavity,  may  here 
produce  an  abscess  cavity  of  great  size.  Fitz  has  pointed 
out  that  disseminated  fat  necrosis  is  uncommon  with 
suppurative  pancreatitis  though  almost  constantly  found 
in  association  with  the  hemorrhagic  and  gangrenous 
lesions. 

The  lesion  usually  described  as  acute  hemorrhagic 
pancreatitis  has  not  the  characters  of  an  inflammatory 
process.  Wide-spread  necrosis  of  pancreatic  parenchyma 
is  primary  and  such  inflammatory  changes  as  occur  are 

•  Chiari :    Wiener  med.  Woch.,  1880,  xxx,  139,  164. 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         121 

found  only  at  the  margin  of  the  necrotic  tissue.  A 
clearer  understanding  of  the  nature  of  the  disease  would 
doubtless  result  if  the  term  hemorrhagic  necrosis  of  the 
pancreas  were  used  in  place  of  acute  hemorrhagic 
pancreatitis. 

Similar  lesions  do  not  occur  in  other  organs  save, 
perhaps,  in  the  stomach,  where  impaired  vitality  of  the 
mucosa  is  followed  by  necrosis  and  subsequent  ulceration, 
often  with  hemorrhage  brought  about  by  action  of  the 
gastric  juice  upon  the  injured  tissue.  The  analogy  is 
significant  for  the  pancreas,  too,  contains  an  active  pro- 
teolytic enzyme  which  unrestrained  is  capable  of  destroy- 
ing tissue.  The  peculiar  necrosis  which  affects  the  pan- 
creatic parenchyma  is  doubtless  referable  to  the  trypsin 
which  is  contained  in  the  pancreatic  cells.  Numerous 
studies  have  clearly  demonstrated  that  the  necrosis  of  fat 
which  accompanies  hemorrhagic  necrosis  of  the  pancreas 
is  caused  bj^  a  second  enzyme,  the  fat-splitting  enzyme 
of  the  pancreatic  juice. 

Eecognition  of  the  truth  that  necrosis  of  tissue  is  the 
essential  feature  of  the  acute  hemorrhagic  lesion,  ex- 
plains the  relation  of  hemorrhagic  to  gangrenous  pan- 
creatitis. In  individuals  who  die  within  from  one  to 
three  or  four  days  after  onset  of  the  symptoms,  the  gland 
is  swollen  and  hemorrhagic,  but  when  death  occurs  after 
a  longer  period  there  are  changes  in  the  hemorrhagic 
tissue  so  that  it  becomes  black  and  gangrenous  in  appear- 
ance. It  has  been  customary  to  describe  as  separate  dis- 
eases hemorrhagic  and  gangrenous  pancreatitis,  whereas 
in  both  the  underlying  change  is  death  of  pancreatic 
parenchyma,  and  the  two  conditions  represent  two  stages 
of  the  same  lesion. 


122  DISEASE  OF  THE  PANCREAS 

Pancreatic  Hemorrhage. — Hemorrhage  occurring  into 
the  substance  of  the  gland  may  be  caused  by  a  variety  of 
factors  which  present  nothing  peculiar  to  the  organ. 
Vessels  may  be  ruptured  by  traumatism,  and  here,  as 
elsewhere,  hemorrhage  may  accompany  tumors ;  the  con- 
tents of  pancreatic  cysts  are  not  infrequently  bloody. 
Hemorrhage  of  such  character,  as  well  as  the  minute 
hemorrhages  observed  in  association  with  purpura, 
eclampsia,  and  acute  infectious  diseases  are  dependent 
upon  factors  which  determine  their  occurrence  in  other 
organs  and  have  little  in  common  with  the  peculiar 
hemorrhagic  lesion  to  which  the  pancreas  is  subject. 

Hemorrhage  into  the  pancreas  occurring  in  an  indi- 
vidual previously  supposed  to  be  in  good  health  may 
be  the  only  lesion  found  to  explain  the  fatal  termination 
of  an  illness  lasting  only  a  few  hours.  The  literature 
of  pancreatic  affections  contains  numerous  examples  of 
so-called  pancreatic  apoplexy  of  which  the  sudden  onset 
and  rapidly  fatal  end  suggest  an  analogy  with  the  more 
frequent  cerebral  hemorrhage.  The  quantity  of  blood 
escaping  from  the  vessels  does  not  bear  a  direct  relation 
to  the  severity  of  the  lesion.  Such  a  condition  has  been 
described  by  Spiers,^  in  1866,  and  since,  other  writers, 
notably  Zenker,^  Prince,^  Draper,^  and  Seitz,^^  have  re- 
corded additional  instances. 

In  some  cases  cited  as  examples  of  pancreatic  hemor- 


"  Spiers :  Quoted  by  Seitz. 

'Zenker:  Berliner  klin.  Woeh.,  1874,  xi,  611;  Deutsche  Zeit.  f. 
prakt.  Med.,  1874,  351. 

"Prince:  Boston  Med.  and  Surg.  Jour.,  1882,  evii,  28,  55. 
"Draper:    Boston  Med.  and  Surg.  Jour.,  1886,  cxv,  393. 
"Seitz:  Zeit.  f.  klin.  Med.,  1892,  xx,  1,  203,  311. 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         123 

rhage  it  is  improbable,  as  Seitz  points  out,  that  the  pan- 
creatic lesion  has  been  in  reality  the  cause  of  death,  and 
in  the  cases  described  by  Eeubold  and  Eehm,  after  death 
from  poisoning  with  morphia,  after  strangling,  or  after 
hemorrhage  from  the  femoral  vein,  the  interstitial  tissue 
of  the  gland  and  its  immediate  vicinity  has  been  the  seat 
of  such  moderate  hemorrhagic  infiltration  that  extravasa- 
tion of  blood  may  have  been  the  result  of  post-mortem 
self -digestion ;  Chiari  has  described  such  insignificant 
hemorrhage  occurring  perhaps  just  before  death  (see  p. 
86).  There  remains,  however,  a  considerable  number 
of  cases  where,  following  sudden  death,  a  careful  autopsy 
has  disclosed  no  noteworthy  disease  other  than  an  exten- 
sive hemorrhagic  lesion  of  the  pancreas. 

Klebs  thought  that  hemorrhage  occurring  in  the  ab- 
sence of  inflammatory  changes  might  be  due  to  corrosive 
action  of  the  pancreatic  juice  upon  the  blood-vessels. 
Fitz  recalls  the  observation  that  fluids  injected  into  the 
arteries  of  a  dead  body  are  prone  to  escape  in  the  neigh- 
borhood of  the  pancreas.  It  has  been  maintained  by 
Seitz  that  in  a  limited  number  of  cases  arterial  sclerosis 
explains  the  occurrence  of  hemorrhage,  but  the  only 
evidence  in  support  of  this  supposition  is  the  occasional 
association  of  the  two  conditions. 

The  explanation  of  hemorrhage  secondary  to  inflam- 
matory changes  in  the  gland  has  been  much  discussed. 
What  has  been  designated  acute  inflammation  is  accom- 
panied by  escape  of  blood  into  the  interstitial  tissue,  and 
the  condition  has  been  supposed  to  resemble  hemorrhagic 
inflammation  in  other  organs.  Inflammation  is  regarded 
as  primary  and  the  hemorrhage  its  consequence.  When 
both  inflammation  and  hemorrhage  coexist,  the  difficulty 


124  DISEASE  OF  THE  PANCREAS 

of  deciding  whicli  preceded  the  other  is  obviously  great, 
— for  should  extensive  hemorrhage  occur,  proximity  to 
the  intestine  exposes  the  hemorrhagic  tissue  to  infection 
and  consequent  suppuration.  Both  hemorrhage  and 
acute  inflammation  being  present,  it  is  not  possible  to 
determine  which  antedated  the  other. 

Seitz  (1892),  reviewing  older  literature  and  citing  the 
cases  of  Losclmer,  Oppolzer,  Amidon,  Osier  and  Hughes, 
Hirschberg  and  Birch-Hirschfeld,  finds  no  evidence  of 
pancreatic  inflammation,  and  concludes  that  inflammation 
is  not  a  demonstrable  cause  of  bulky  hemorrhage  into 
the  organ.  Nevertheless  the  occurrence  of  necrosis  of 
pancreatic  parenchyma  in  these  cases  cannot  be  ex- 
cluded. Recent  literature  of  the  subject  contains  no 
well-defined  instance  of  simple  pancreatic  hemorrhage. 
In  a  case  of  Simpson,^  ^  described  as  an  instance  of  pan- 
creatic hemorrhage,  a  gall-stone  has  been  found  lodged 
at  the  duodenal  orifice  of  the  common  bile  duct.  Since 
a  stone  in  this  position,  as  it  will  be  shown,  may  cause 
hemorrhagic  necrosis  of  the  pancreas,  the  case  cannot 
be  regarded  as  an  example  of  simple  hemorrhage.  Pan- 
creatic apoplexy  analogous  to  cerebral  apoplexy  and 
referable  perhaps  to  arterial  disease  occurs  rarely  if 
at  all,  and  described  instances  are  doubtless  examples 
of  hemorrhagic  necrosis  of  the  gland. 

Experimental  Hemorrhagic  Necrosis. — So-called 
hemorrhagic  pancreatitis  has  been  produced  experi- 
mentally by  the  injection  of  a  variety  of  irritating  sub- 
stances into  the  i)ancreas.  Thiroloix  '^  injected  several 
drops  of  deliquescent  chloride  of  zinc  into  the  duct  of 

"  Simpson :  Edinburgh  Med.  Jour.,  1S97,  ii,  245. 
"  Thiroloix  :  Thesis,  Paris,  1892. 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         125 

Wirsung  in  a  dog.  Death  occurred  suddenly  after  a 
short  interval,  and  the  pancreas  was  represented  by  what 
appeared  to  be  a  blackish  clot.  Hlava^"  injected  arti- 
ficial gastric  juice  into  the  pancreatic  duct.  This  fluid, 
containing  hydrochloric  acid  in  the  proportion  of  one 
to  one  thousand  caused  death  in  three  days ;  the  pancreas 
was  hyperaemic  and  in  the  fat  of  the  omentum  and 
mesentery  were  numerous  foci  of  necrosis.  Death  on 
the  tenth  day  followed  the  injection  of  five  cubic  centi- 
metres of  artificial  gastric  juice  with  hydrochloric  acid, 
four  to  one  thousand ;  the  pancreas  was  the  seat  of  hemor- 
rhagic infiltration,  and  the  omentum  and  mesentery  con- 
tained foci  of  fat  necrosis.  He  suggests  that  in  human 
cases  hyperacid  gastric  juice  may  be  forced  by  antiperi- 
staltic action  of  the  intestine  into  the  pancreatic  duct, 
thus  causing  the  condition.  Hlava  has  produced  a 
hemorrhagic  lesion  of  the  gland  by  injecting  cultures  of 
Bacillus  coli,  Bacillus  lactis  aerogenes,  and  Bacillus  cap- 
sulatus  of  Friedlander,  but  thinks  that  the  change  is 
caused  by  the  acid  products  of  these  organisms. 

By  the  injection  of  the  ferment,  j^apaine  (0.2  Gm. 
in  30  c.c.  of  water),  into  the  pancreatic  duct  of  a  dog, 
Carnot^^  caused  the  death  of  the  animal  in  twenty-five 
hours;  the  pancreas  was  everywhere  infiltrated  with 
blood,  but  there  was  no  necrosis  of  fat.  Smaller  doses 
did  not  produce  hemorrhagic  lesions.  The  same  writer 
produced  so-called  hemorrhagic  pancreatitis  by  the  in- 
jection of  the  diphtheria  toxin  into  the  pancreatic  duct 
of  a  rabbit. 

"Hlava:  Bull,  internat.  de  TAead.  des  sciences  de  Boheme,  1898; 
Arch.  Bohem,  1890,  iv,  139.  (Cited  by  Katz  and  Winkler,  loc.  cit., 
p.   191.) 

'■'  Cai'iiol :  Thesis,  Paris,  1S98. 


126  DISEASE  OF  THE  PANCREAS 

Varied  and  successful  experiments  have  been  per- 
formed by  Flexner.^^  Hydrocbloric  acid  varying  in 
strength  in  different  instances  from  one-half  of  1  to  2 
per  cent.,  and  in  amount  from  three  to  eight  cubic 
centimetres,  injected  into  the  pancreatic  duct,  caused 
in  six  of  ten  experiments  hemorrhagic  lesions  of  the 
gland,  accompanied  in  five  instances  by  focal  fat  ne- 
crosis. Such  lesions  were  characterized  by  hemor- 
rhage, necrosis  of  the  parenchyma,  and  accumulation  of 
inflammatory  products.  In  three  experiments  death  fol- 
lowed the  operation  within  twenty-four  hours.  In 
four  experiments  purulent  or  chronic  interstitial  inflam- 
mation resulted.  Hemorrhagic  lesions  were  similarly 
produced  in  dogs  by  nitric  acid  and  chromic  acid.  In  a 
second  series  of  experiments  sodium  hydroxide  (2.5  to 
5  c.c.  of  solutions  varying  in  strength  from  1  to  2  per 
cent.)  was  employed.  Hemorrhagic  lesions  resulted  in 
three  experiments  and  were  accompanied  by  fat  necrosis 
in  two.  Suspensions  of  bacteria  were  used  in  a  third 
series.  Hemorrhagic  lesions  were  caused  by  Bacillus 
pyocyaneus  and  by  Bacillus  diphtheriae.  In  two  experi- 
ments the  lesion  followed  the  injection  of  5  c.c.  of  a  2 
per  cent,  solution  of  formalin  into  the  duct  and  was 
associated  with  fat  necrosis.  Flexner  and  Pearce  ^^  have 
subsequently  shown  that  degeneration,  hemorrhage,  and 
emigration  of  leucocytes  develop  with  great  rapidity, 
occurring  within  one  to  two  hours  after  the  introduction 
of  such  an  irritant  as  artificial  gastric  juice. 


"Floxner:  Contributions  to  ilio  Science  of  Medicine.  Dedicated 
to  William  H.  Welch.     Johns  Hopkins  Hosp.  Rep.,  1900,  ix,  743. 

"  Flexner  and  Pearce :  Univ.  of  Pennsylvania  Med.  Bull.,  1901,  xiv, 
!!):{. 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         127 

Gulecke/''^  and  Sailer  and  Speese  ^^  have  produced  in 
dogs  similar  quickly  fatal  lesions  with  fat  necrosis  by 
injection  of  sweet  oil  into  the  pancreatic  duct  immediately 
followed  by  ligation  of  the  duct ;  fatty  acids  and  sodium 
soaps  of  these  acids  have  been  successfully  used,  but 
glycerin  is  ineffective  (Hess  ^^). 

It  is  difficult  to  define  any  common  character  of  these 
substances,  save  their  power  to  injure  the  tissue  with 
which  they  come  into  contact.  A  variety  of  bland  sub- 
stances have  been  tested  with  negative  result;  these  in- 
clude blood,  blood  serum  (Flexner  and  Pearce), 
agar-agar  (Flexner  ^o),  paraffin  (Thiroloix,  Hess),  emul- 
sion of  starch  (Hess). 

Since  active  trypsin  is  not  found  in  the  normal  gland 
attempts  have  been  made  to  produce  the  lesion  by  acti- 
vating with  enterokinase  the  trypsinogen  which  is  pres- 
ent, but  Polya^^  and  Williams  and  Busch  22  have  failed 
to  produce  hemorrhagic  necrosis  by  injection  of  entero- 
kinase into  the  pancreatic  duct. 

ETIOLOGY. 

Hemorrhagic  necrosis  of  the  pancreas  occurs  more 
frequently  in  men  than  in  women.  Of  121  cases  of  so- 
called  hemorrhagic  and  gangrenous  pancreatitis  collected 

"  Gulecke :  Arbeiten  a.  d.  chir.  Klin.  d.  Konig.  Univ.,  Berlin,  1906, 
xviii,  368. 

"  Sailer  and  Speese :  Trans,  of  the  Assoc,  of  Anaeriean  Phys., 
1908,  xxiii,  540. 

'"  Hess :  Miinehener  med.  Woch.,  1903,  1,  1905. 

'"Flexner:    Jour,  of  Exper.  Med.,  1906,  viii,  167. 

""Polya:    Berliner  klin.  Woch.,  1906,  xUii,  1562. 

'^  Williams  and  Busch :  Trans,  of  the  Assoc,  of  American  Phys., 
1907,  xxii,  304. 


128  DISEASE  OF  THE  PANCREAS 

by  Peiser,^^  79  were  in  men,  whereas  only  42  were  in 
women.  Of  41  instances  of  the  hemorrhagic  lesion  col- 
lected b}^  Korte,-'*  27  were  in  males  and  4  in  females ;  of 
40  examples  of  gangrenous  lesion,  21  were  in  males  and 
19  in  females.  The  disease  not  infrequently  attacks  in- 
dividuals who  have  apparently  been  in  good  health; 
individuals  with  abundant  fat  are,  it  is  claimed,  particu- 
larly susceptible. 

The  experiments  which  have  been  cited  show  that  a 
variety  of  substances  injected  into  the  duct  of  the  pan- 
creas cause  hemorrhagic  inflammation.  How  far  they 
can  be  used  to  explain  the  pathogenesis  of  human  cases 
is  doubtful.  The  suggestion  of  Hlava  that  gastric  juice 
may  be  driven  by  antiperistaltic  action  of  the  intestine 
into  the  ducts  is  not  supported  by  any  evidence. 

Bacteriology. — No  relation  between  hemorrhagic 
necrosis  of  the  pancreas  and  bacterial  invasion  from  the 
intestine  has  been  demonstrated.  Welch  ^^  cultivated 
Bacillus  coli  from  foci  of  fat  necrosis  accompanying  acute 
hemorrhagic  pancreatitis,  but  reached  the  conclusion  that 
the  organism  penetrated  the  dead  tissue  after  the  lesion 
had  been  produced.  In  cases  of  hemorrhagic  pancrea- 
titis Hlava  found  Bacillus  coli  associated  with  the  pneu- 
mococcus  and  other  diplococci ;  Cutler  ^^'  and  Reynolds 
and  Moore  ^^  have  also  isolated  the  colon  bacillus.  Leon- 
hardt  -^  in  one  case  found  staphylococci,  streptococci,  and 

''Peiser:  Deutsche  Zeit.  f.  Chir.,  1902,  Ixv,  302. 
"  Korte :    Chirurgisehen  Krankheiten  des  Pankreas,  Deutsche  Chir- 
urgie,  Stuttgart,  1898. 

"Welch:  Med.  News,  1891,  lix,  (509. 

**  Cutler:    Boston  Med.  and  Surg.  Jour.,  1895,  cxxxii,  354. 
"  Reynolds  and  Moore :  British  Med.  Jour.,  1898,  i,  1335. 
"'Leonhardt:    Virchow's  Arch.,   1900,  clxii,  299. 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         129 

two  unidentified  bacilli,  while  Jackson  and  Ernst,  in  a 
case  of  Fitz's,  isolated  four  species  of  bacteria.  Pon- 
fick  29  and  Marx  ^'^  each  cultivated  a  bacillus  closely  re- 
lated to  the  colon  bacillus,  but  not  identical  with  it  nor 
with  one  another.  The  variable  and  inconstant  result  of 
bacteriological  examination  indicates,  as  almost  all  the 
writers  cited  agree,  that  these  various  organisms  are  not 
the  etiological  factor  in  producing  the  lesion,  but  are 
merely  secondary  invaders  of  injured  tissue.  It  is  sig- 
nificant that  the  necrotic  parenchyma  may  contain  no 
micro-organisms  even  though  it  is  exposed  to  bacterial 
invasion  from  the  duodenum. 

The  Association  of  Acute  Pancreatitis  and  Choleli- 
thiasis.— The  etiology  of  hemorrhagic  necrosis  of  the 
pancreas  has  remained  obscure  until  a  series  of  cases 
recently  studied  has  demonstrated  a  relationship  between 
the  lesion  and  cholelithiasis.  Since  the  common  bile 
duct  and  the  duct  of  Wirsung  unite  to  form  the  diverticu- 
lum of  Vater  before  they  reach  the  duodenum,  changes  in 
the  one  duct  may  be  transmitted  to  the  other,  thus  pro- 
ducing secondary  lesions  of  the  liver  or  pancreas.  The 
association  of  pancreatic  disease  with  alterations  of  the 
bile  passages  has  been  noted  by  Korte,  Oser,^^  Lance- 
reaux,^^  and  other  writers. 

My  attention  was  directed  to  the  relationship  between 
pancreatic  necrosis  and  the  impaction  of  a  calculus  in  the 

"°  Ponfiek :  Berliner  klin.  Wocli.,  1896,  xxxiii,  365. 

'"Marx:  Virehow's  Arch.,  1901,  elxv,  290. 

"  Oser :  Die  Erkrankungen  des  Pankreas.  NothnageFs  Spec.  Path, 
u.  Ther.,  Vienna,  1898,  xvii. 

^Lancereaux:  Traite  des  maladies  du  foie  et  du  pancreas,  Paris, 
1899. 

9 


130  DISEASE  OF  THE  PANCREAS 

common  bile  duct  by  the  following  case  ^^   studied  at 
autopsy : 

Case  I. — L.  F.,  male,  aged  forty-seven  years,  admitted  to  the  Johns 
Hopkins  Hospital,  in  the  service  of  Dr.  Osier,  had  suffered  somewhat 
frequently  with  pain  after  eating,  distention,  and  rarely  with  nausea 
and  vomiting.  Six  months  before  his  present  illness  he  had  had  an 
attack  of  jaundice. 

The  present  illness  began  eighteen  days  before  admission  to  the 
hospital,  when  the  patient  was  suddenly  seized  with  violent  nausea 
and  vomiting,  accompanied  by  intense  cramp-like  pain  in  the  abdomen. 
The  abdominal  pain,  which  was  not  localized,  remained  severe  during 
four  or  five  days,  and  at  times  there  were  symptoms  of  collapse.  The 
abdomen  was  distended  and  the  bowels  were  constipated  until  the  fifth 
day,  when,  with  the  aid  of  a  purgative,  movement  occurred.  The  stool 
was  normal  in  color.  On  the  third  day  elevation  of  temperature  to 
101.5°  F.  was  noted.  About  the  seventh  day  tenderness  and  slight 
swelling  were  noticed  in  the  right  hypochondriac  and  right  half  of  the 
epigastric  regions.  Since  this  time  the  patient  had  an  irregular  tem- 
perature (100°  to  103°  F.),  with  several  chills.  After  the  first  few 
days  abdominal  pain  and  tenderness  were  not  severe,  but  distention  of 
the  abdomen  gradually  increased.     Jaundice  not  noted. 

On  admission  to  the  hospital  the  conjunctivae  have  a  slightly  yellow 
cast.  The  lower  margin  of  a  mass  which  can  be  felt  to  the  right  of  the 
median  line  is  at  the  level  of  the  umbilicus  and  descends  with  inspira- 
tion. The  leucocytes  number  eighteen  thousand.  The  urine  has  specific 
gravity  of  1017  and  does  not  reduce  Fehling's  solution. 

On  the  second  day  after  admission  a  stool  passed  was  of  golden 
yellow  color.  On  the  third  day  the  leucocytes  numbered  nineteen  thou- 
sand five  hundred.  The  temperature  rose  gradually,  reaching  a  maxi- 
mum of  104°  F.     A  liquid  stool  of  ochre-yellow  color  was  passed. 

The  diagnosis  of  suppurative  pancreatitis  was  made  by  Dr.  Blood- 
good,  and  an  operation  for  its  relief  was  performed  under  cocaine 
ana?sthesia.     After  incising  the  great  omentum  between  the  stomach  and 


"Opie:  American  Jour,  of  the  Med.  Sciences,  1901,  cxxi,  27. 


I'lG.  20. — Gall-stones  from  Case  I  (actual  size).  The  calculus  removed  from  the  common 
liile  duct  near  its  duodenal  orifice  is  placed  in  the  centre,  and  those  from  the  gall-bladder 
surround  it. 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         131 

transverse  colon  an  abscess  cavity  was  entered.  Gnimous,  purulent 
fluid  containing  necrotic  particles  was  evacuated.  A  rubber  drainage- 
tube,  packed  about  with  gauze,  was  inserted  into  the  wound.  After 
operation  the  pulse  remained  weak,  and  death  followed  at  the  end  of 
about  four  houx-s.  The  duration  of  the  fatal  illness  was  twenty-one 
days. 

Autopsy. — The  body  is  that  of  a  large-framed,  muscular  man  with 
abundant  subcutaneous  fat.  The  omentum,  which  contains  a  large 
quantity  of  fat,  is  thickly  studded  with  conspicuous  opaque,  white  areas, 
which  are  present  as  well  in  the  fat  of  the  mesentery,  in  the  subperi- 
toneal fat  of  the  anterior  abdominal  wall,  over  the  bladder,  over  the 
kidneys,  and  about  the  colon. 

An  immense  abscess  cavity  occupies  the  site  of  the  lesser  peritoneal 
cavity;  the  foramen  of  Winslow  is  closed.  The  walls  of  the  cavity  are 
very  irregular  and  ragged,  and  have  a  necrotic  appearance,  in  general 
opaque  and  gray,  occasionally  black.  This  blackish-gray  appearance 
extends  only  a  short  distance  below  the  surface,  and  where  the  wall  is 
formed  by  fat  gives  place  to  numerous  foci  of  opaque,  white  color. 
The  retroperitoneal  fat  in  front  of  the  left  kidney  and  psoas  muscle 
has  been  eroded,  and  an  extension  of  the  cavity  passes  behind  the 
jejunum  near  its  junction  with  the  duodenum.  Overlying  the  pan- 
creas is  a  gTeat  mass  of  reddish-black  altered  blood.  The  cavity  con- 
tains at  least  500  c.e.  of  fluid  reddish-gi-ay  material,  in  which  are  fat 
droplets  and  black  necrotic  particles. 

The  gall-bladder  is  bound  by  numerous  adhesions  to  the  duodenum 
and  stomach.  Its  walls  are  thickened  and  it  is  much  distended,  con- 
taining viscid,  yellow  bile  and  more  than  one  hundred  brown,  faceted 
calculi,  varying  in  diameter  from  0.5  to  1  cm.  (see  Fig.  20).  The  he- 
patic, cystic,  and  common  duets  are  much  dilated.  On  opening  the 
duodenum  a  stone  is  felt  below  the  mucous  membrane,  situated  in  the 
common  bile  duct  near  its  tennination.  It  is  7  mm.  in  diameter,  and 
resembles  those  present  in  the  gall-bladder.  The  pancreatic  duot 
unites  with  the  common  bile  duct  at  a  point  7  mm.  from  the  duodenal 
orifice.     The  pancreatic  duet  is  not  distended. 

The  pancreas  occupies  the  posterior  wall  of  the  abscess  cavity  of 
the  lesser  peritoneum,  and  is  covered  by  the  mass  of  changed  coag-ulated 


132  DISEASE  OF  THE  PANCREAS 

blood,  above  described.  The  organ  is  in  great  part  well  preserved.  The 
interstitial  tissue  has  a  dull  reddish,  in  places  hemon-hagic,  appearance, 
and  contains  conspicuous  opaque  yellow  areas  of  irregular  shape. 
Where  the  anterior  surface  of  the  head  and  body  is  in  contact  with  the 
overlying  material  there  is  a  superficial  zone  of  soft,  grayish,  necrotic 
appearance. 

The  other  organs — heart,  lungs,  spleen,  stomach,  intestines,  and  kid- 
neys— present  no  noteworthy  alteration. 

Histological  Examination. — The  interstitial  tissue  of  the  pancreas 
is  much  increased  and  wide  bands  of  fibrous  tissue  separate  groups 
of  lobules.  Numerous  cells  filled  with  brownish-yellow  iron-containing 
pigment  afford  evidence  of  fonner  hemon-hage.  In  a  few  places  well- 
preserved  red  corpuscles  are  diffusely  scattered  in  the  tissue.  In  a 
zone  below  the  surface  of  the  gland,  nuclei  no  longer  stain,  and  the 
architecture  of  the  glandular  tissue  is  only  obscurely  distinguishable. 
A  thick  band  of  newly  formed  fibrous  tissue,  containing  an  occasional 
acinus  or  duct,  separates  the  necrotic  parenchyma  from  that  which  is 
still  intact.  The  mass  covering  the  pancreas  is  found  to  consist  of 
altered  blood;  upon  and  immediately  below  its  surface  are  numerous 
polynuclear  leucocytes. 

Bacteriological  Examination. — Cultures  from  the  blood  contained 
in  the  heart,  from  the  lung,  and  from  the  liver,  studied  by  Mr.  V.  H. 
Bassett,  were  found  to  contain  Bacillus  coli.  A  plate  culture  from  the 
material  covering  the  pancreas,  and  forming  part  of  the  abscess  wall, 
contained  Bacillus  coli,  Bacillus  lactis  aerogenes,  and  Bacillus  proteus 
vulgaris. 

Anatomical  Diagnosis. — Cholelithiasis;  calculus  lodged  in  the  com- 
mon bile  duct  near  its  orifice;  slight  jaundice.  Old  hemoiThage  within 
and  about  the  pancreas,  with  localized  necrosis  and  increase  of  fibrous 
tissue  (hemorrhagic  necrosis  in  process  of  healing) ;  necrosis  of  fat  of, 
the  pancreas,  greater  and  lesser  omentum,  mesentery,  and  subperitoneal 
tissue  of  the  abdominal  wall;  peripancreatic  abscess  limited  by  the 
lesser  peritoneal  cavity.     Laparotomy  wound. 

The  second  attack  referable  to  the  passage  of  gall- 
stones began  suddenly,  three  weeks  before  death,  with 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         133 

severe  nausea  and  vomiting.  Tenderness  was  present  in 
the  right  hypochondriac  region,  and  on  admission  to  the 
hospital  the  patient  was  slightly  jaundiced.  Autopsy 
disclosed  a  small  gall-stone  lodged  in  the  common  bile 
duct,  a  short  distance  from  its  orifice.  The  lesser  peri- 
toneal cavity  was  the  site  of  an  abscess,  the  walls  of 
which  were  formed  in  large  part  by  necrotic  fat ;  the  sub- 
peritoneal tissue  was  studded  with  conspicuous  opaque, 
white  foci  of  fat  necrosis.  The  pancreas  was  in  general 
well  preserved,  but  its  interstitial  tissue  was  increased 
and  gave  evidence  of  having  been  the  seat  of  hemorrhage. 
The  anterior  surface  of  the  pancreas  was  covered  by  a 
considerable  quantity  of  old,  clotted  blood,  having  the 
dark  appearance  of  gangrenous  tissue  and  forming  the 
tumor  mass,  which  was  palpable  during  life.  A  super- 
ficial zone  of  glandular  parenchyma  in  contact  with  this 
material  was  necrotic.  Since  jaundice  was  slight  and  the 
hepatic  duct  was  not  dilated,  it  is  probable  that  the  cal- 
culus produced  only  temporary  obstruction  of  the  two 
ducts. 

Similar  cases  are  recorded  in  the  literature  of  the 
subject.  The  following  cases  in  which  a  gall-stone  has 
passed  into  the  duodenum  just  before  death  or  has  been 
impacted  at  the  orifice  of  the  diverticulum  of  Vater  are 
especially  noteworthy : 

Case  A.  (Thayer.^^) — During  sixteen  months  a  man,  aged  sixty 
years,  had  suffered  attacks  of  pain,  followed  by  jaundice.  He  was  sud- 
denly attacked  with  severe  pain  in  the  left  hypochondriac  and  epigas- 
tric regions.  Collapse  preceded  death,  which  followed  within  twenty- 
four  hours  after  the  onset  of  symptoms.     The  thickened  gall-bladder 

""  Thayer :  Boston  Med.  and  Surg.  Jour.,  1889,  exxi,  506. 


134  DISEASE  OF  THE  PANCREAS 

contained  over  a  hundred  calculi.  The  common  bile  duet  was  dilated 
to  the  size  of  the  little  finger,  and  in  the  duodenum  was  a  calculus  tlie 
size  of  a  hazel-nut.  The  pancreas  was  large,  grayish-pink,  mottled 
with  reddish-brown.     There  were  foci  of  fat  necrosis. 

Case  B.  (Day.^'^) — For  several  months  the  patient,  male,  aged 
forty-nine  years,  had  suffered  with  pain  in  the  epigastrium  and  right 
hypochondrium,  and  once  he  was  jaundiced.  About  sixteen  hours 
before  death  he  was  suddenly  attacked  with  vomiting  and  severe  epi- 
gastric pain,  followed  by  collapse.  "The  gall-bladder  contained  one 
small  concretion  of  inspissated  bile;  two  others  were  lodged  in  the 
duodenal  extremity  of  the  common  duct."  The  body  and  tail  of  the 
pancreas  were  enlarged  and  infiltrated  with  blood.  In  the  neighborhood 
of  the  gland  were  foci  of  fat  necrosis.  S. 

Case  C.  (Cutler.'") — For  fifteen  years  the  patient,  a  woman, 
aged  fifty-eight  years,  had  suffered  with  severe  attacks  of  indigestion, 
on  one  occasion  followed  by  jaundice.  Four  days  before  death  she 
was  seized  with  pain  in  the  right  hypochondrium,  accompanied  by 
vomiting,  chill,  and  fever,  and  followed  by  jaundice.  A  small  gall- 
stone was  found  at  the  outlet  of  the  common  duct;  others  were  present 
in  the  gall-bladder.  The  pancreas  was  enlarged,  surrounded  and  in- 
filtrated with  blood.  Numerous  foci  of  fat  necrosis  were  seen  in  its 
neighborhood. 

Case  D.  (Kennan.^^) — A  woman,  aged  thirty-eight  years,  was 
suddenly  seized  forty-two  hours  before  death  with  vomiting  and  pain 
in  the  upper  part  of  the  abdomen,  followed  by  symptoms  of  collapse. 
A  gall-stone,  about  the  size  of  a  pea,  was  found  projecting  from  the 
orifice  of  the  common  duct  into  the  duodenum.  The  pancreas  was 
enlarged,  and  exhibited  intense  injection  suggesting  inflammatory 
change. 

Case  E.  (Simpson.^") — A  man,  aged  forty-one  yeai-s,  was  sud- 
denly attacked  witli  vomiting  and  severe  abdominal  pain.  Collapse 
preceded  death,   which  occurred  at  the  end  of  forty-four  hours.     A 

'°  Day :   Boston  RDed.  and  Surg.  Jour.,  lcS92,  exxvii,  569. 

"  Loc.  cit. 

"  Kennan  :  British  Med.  Jour.,  1896,  ii,  1442.    ^ 

"  hoc.  cit. 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         135 

small  cubical  gall-stone  projected  from  the  end  of  the  common  duct  into 
the  duodenum;  similar  concretions  were  found  in  the  gall-bladder.  The 
pancreas  was  greatly  enlarged,  weighing  525  Gm.,  and  was  mottled 
with  areas  of  reddish-brown  color,  due  to  hemorrhagic  infiltration  of  its 
interstitial  tissue.  The  organ  was  surrounded  by  semifluid,  clotted 
blood,  of  dark-brown  color.  The  intima  of  the  splenic  artery  was  of  a 
dirty-blue  color,  and  was  apparently  necrotic  about  two  centimetres 
from  the  aorta;  Simpson  regards  this  vessel  as  the  source  of  the 
hemorrhage,  although  he  does  not  state  that  rupture  had  occurred. 

In  1903  I  collected  from  the  literature  of  the  subject 
thirty-seven  cases  of  so-called  hemorrhagic  and  gangren- 
ous pancreatitis  occurring  in  association  with  cholelithi- 
asis. Among  one  hundred  and  five  recorded  cases 
described  as  acute  pancreatitis  EgdahP^  found  cholelithi- 
asis in  forty-four  instances  (42  per  cent.).  The  propor- 
tion of  such  cases  is  probably  greater,  for  the  contents 
of  the  gall-bladder  and  bile  passages  had  been  doubtless 
overlooked  or  unrecorded  in  many  instances. 

The  cases  which  have  been  cited  suggest  no  process 
nor  mechanism  by  which  a  lesion  of  the  pancreas  results 
from  the  presence  of  a  calculus  in  the  common  bile  duct 
near  its  duodenal  orifice.  The  autopsy  upon  a  second 
case  of  hemorrhagic  necrosis  of  the  pancreas  studied  in 
the  partial  light  of  that  already  described  (Case  I)  has 
demonstrated  a  mechanism*^  by  which  a  small  biliary 
calculus  produces  a  destructive  lesion  of  the  pancreas 
and  at  the  same  time  has  brought  our  knowledge  of  the 
lesion  into  correlation  with  facts  demonstrable  by  ex- 
perimental means. 

"  Egdahl :  Bull,  of  the  Johns  Hopkins  Hosp.,  1906,  xvii,  265. 
*"  Opie :  The  Etiology  of  Acute  Hemorrhagic  Pancreatitis,  Bull,  of 
the  Johns  Hopkins  Hosp.,  1901,  xii,  182. 


136  DISEASE  OF  THE  PANCREAS 

Case  II. — Mr.  T.,  a  corpulent  man  of  robust  appearance,  aged 
forty-eight  yeai^s,  had  been  for  several  years  subject  to  attacks  of  pain 
in  the  epigastrium.  After  luncheon,  nine  days  before  the  fatal  ter- 
mination of  his  illness,  he  was  suddenly  seized  with  severe  pain,  in  the 
abdomen,  accompanied  by  nausea.  The  pain  persisted,  but  during  the 
week  following  he  took  his  meals  regularly  and  slept  as  usual.  About 
noon  of  the  day  preceding  his  admission  to  the  Johns  Hopkins  Hos- 
pital the  pain  became  so  severe  that  the  repeated  administration  of 
morphia  gave  little  relief.  When  seen  by  Dr.  Halsted  ^  at  nine  o'clock 
in  the  evening  he  was  in  great  pain.  Though  his  pulse  was  full  and 
regular,  the  skin  was  markedly  cyanosed.  The  following  morning  oper- 
ation was  performed  by  Dr.  Halsted.  On  opening  the  abdomen  numer- 
ous foci  of  fat  necrosis  were  seen  upon  the  omentum  and  in  the  mesen- 
tery. The  pancreas  was  examined  through  an  opening  made  in  the 
gastrocolic  omentum,  and  the  tissue  over  it  was  found  infiltrated  with 
blood-stained  fluid.  Slight  distention  of  the  common  bile  duct  was 
noted.  Blood-stained  fluid  was  removed  from  the  abdominal  cavity, 
and  gauze,  packed  through  the  wound,  was  brought  into  contact  with 
the  head  of  the  pancreas.     Death  oceuiTed  twenty-three  hours  later. 

Autopsy. — The  body  is  that  of  a  large  man  with  abundant  sub- 
cutaneous fat.  Fat  is  present  in  large  amount  in  the  omentiun,  mesen- 
tery, and  subperitoneal  tissue,  and  is  thickly  studded  with  small,  opaque, 
white  ai'eas  of  fat  necrosis.  The  pancreas  is  represented  by  a  swollen 
mass  of  almost  uniform  black  or  reddish-black  color.  The  head  of  the 
organ  is  partly  normal  in  appearance,  but  tissue  which  is  in  immediate 
contact  with  this  well-preserved  gland  substance  is  soft  and  black, 
mottled  here  and  there  with  small  areas  of  dull  i-ed.  The  distal  half  of 
the  organ  shows  a  similar  mottling  of  black  and  reddish  areas,  among 
which  are  islands  of  yellowish,  relatively  well-preseiTed  tissue.  The 
intima  of  the  splenic  vein  is  mottled  yellow,  blackish,  and  red  as  the 
result  of  changes  in  the  underlying  tissue,  and  in  the  lumen  is  a  mixed 
red  and  yellow  thrombus  mass. 

The  duodenum  has  been  opened  and  the  common  orifice  of  the  bile 
and   pancreatic    ducts   examined.     The   papilla   is   prominent,   but   its 

"  The  clinical  history  of  this  ease  has  been  recorded  by  Dr.  Halsted : 
Bull,  of  the  Johns  Hopkins  Hosp.,  1901,  xii,  179. 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         137 

orifice  is  of  small  size,  measuring  one  mm.  in  diameter.  The  common 
bile  duct,  which  near  its  termination  is  completely  embedded  in  the  sub- 
stance of  the  pancreas,  is  slightly  distended.  The  gall-bladder  contains 
viscid,  blackish  bile;  no  concretions  are  present.  The  termination  of 
the  pancreatic  duct,  which  is  surrounded  by  the  well-preserved  pan- 
creatic substance  in  contact  with  the  duodenum,  has  been  exposed  by 
dissection,  and  is  found  to  unite  with  the  common  bile  duct  ten  milli- 
metres from  the  summit  of  the  bile  papilla.  A  small  gray-white,  very 
firm  concretion,  three  millimetres  in  diameter,  is  tightly  impacted  in  the 
diverticulum  of  Vater,  from  which  it  cannot  escape  through  the  narrow 
duodenal  opening.  The  pancreatic  duct  and  its  larger  branches,  where 
they  traverse  the  intact  tissue  of  the  head,  are  stained  bright  green 
with  bile. 

In  the  liver  the  portal  veins  are  distended  and  plugged  with  red 
thrombi  which  probably  have  had  their  origin  in  emboli  from  the 
thrombosed  splenic  vein.  The  heart,  lungs,  spleen,  kidneys,  and  adrenal 
glands  present  no  noteworthy  abnormality.  The  urine  contained  in  the 
bladder  does  not  reduce  Fehling's  solution. 

Microscopic  Examination  of  the  Pancreas. — There  is  an  abrupt 
transition  between  intact  parenchyma  in  the  head  of  the  gland  and  the 
adjacent  necrotic  tissue.  The  loose  interlobular  areolar  tissue  is  every- 
where infiltrated  with  red  blood-corpuscles;  polynuclear  leucocytes  are 
present  in  large  numbers  and  often  form  collections  of  considerable 
extent.  Within  the  margin  of  the  intact  tissue  are  several  small  areas 
where  the  parenchyma  presents  an  early  stage  of  necrosis.  Here  the 
secreting  cells  no  longer  stain  with  hematoxylin,  but  assume  a  homo- 
geneous clear  pink  color  with  eosin.  Near  by,  in  similarly  localized 
areas,  the  process  is  more  advanced,  and  the  parenchymatous  cells  are 
replaced  by  formless  material  which,  staining  faintly,  is  mingled  with 
a  few  nuclear  fragments  and  is  densely  infiltrated  with  polynuclear 
leucocytes  and  red  blood-corpiascles. 

The  abrupt  transition  from  relatively  normal  parenchyma  contain- 
ing a  few  islands  of  necrosis  to  wholly  necrotic  tissue  is  marked  by  a 
zone  composed  of  nuclear  fragments,  polynuclear  leucocytes,  red  blood- 
corpuscles,  and  fibrin.  That  part  of  the  tissue  which  macroscopically 
is   black   or   reddish-black   under   the    microscope   is   necrotic;     nuclei 


138  DISEASE  OF  THE  PANCREAS 

are  no  longer  present,  though  the  architecture  of  the  gland  is  still 
obscurely  definable;  both  parenchyma  and  connective  tissue  have  a 
dark-brown  discoloration  due  to  the  presence  of  brown  pigmented 
material  which  appears  to  be  changed  blood. 

Capillary  vessels  in  the  living  tissue  near  the  margin  of  necrosis, 
as  well  as  in  the  immediately  adjacent  necrotic  part,  have  undergone 
hyaline  thrombosis  and  with  Weigert's  stain  for  fibrin  form  conspicuous 
deep-blue,  often  branched,  lines,  as  though  injected.  Examination  with 
high  magnification  demonstrates  at  times  a  close  mesh-work  of  fibrin 
in  these  vessels. 

In  sections  stained  for  bacteria  with  methylene-blue,  with  gentian 
violet,  and  by  Weigert's  method,  none  were  discovered. 

Bacteriological  Examination.— Cultures  from  the  heart's  blood, 
spleen,  and  gall-bladder  give  negative  results.  An  anaerobic  culture 
or  hydrocele  agar-agar  from  the  pancreas  shows  no  growth  after  an 
incubation  of  seventy-two  hours.  An  anaerobic  agar-agar  plate  from 
the  pancrea.s  contains  at  the  end  of  twenty- four  hours  a  single  superficial 
colony  of  a  pigment-forming  coccus  of  which  the  cultural  characters 
indicate  that  it  is  a  contamination  from  the  air.  Streptococcus  pyo- 
genes and  Staphylococcus  epidermis  albus  are  isolated  from  the  perito- 
neal cavity.  The  colon  bacillus  is  present  in  cultures  from  the  liver  and 
kidney. 

Anatomical  Diagnosis. — Cholelithiasis;  calculus  impacted  in  the 
diverticulum  of  Vater,  partially  filling  it,  and  occluding  its  duodenal 
orifice.  Hemorrhagic  necrosis  of  the  pancreas;  disseminated  abdominal 
fat  necrosis.  Thrombosis  of  the  splenic  vein;  embolism  and  thrombosis 
of  branches  of  the  portal  vein. 

The  preceding  autopsy  has  disclosed  a  condition 
which  explains,  I  believe,  the  pathogenesis  of  cases  of  so- 
called  acute  hemorrhagic  and  gangrenous  pancreatitis 
which  are  associated  with  gall-stones.  The  diverticulum 
of  Vater  was  10  mm.  in  length.  Lodged  at  its  apex, 
blocking  the  duodenal  orifice,  was  a  small  calculus  only 
3  mm.  in  diameter,  but  too  small  to  pass  the  narrow 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         139 

opening.  Though  it  occluded  the  duodenal  orifice  of  the 
diverticulum,  it  was  so  small  that  the  orifices  of  the 
common  bile  duct  and  the  pancreatic  duct  were  unob- 
structed. The  two  ducts  were,  therefore,  converted  into 
a  continuous  closed  channel  from  which  it  was  not  pos- 
sible for  either  bile  or  pancreatic  juice  to  escape  (see 
Fig.  9,  i.,  page  15). 

On  dissecting  the  pancreatic  duct  where  it  passed 
through  the  unchanged  parenchyma  in  contact  with  the 
duodenum  it  was  found,  like  the  bile  duct,  to  be  stained 
bright  green  with  bile.  Where,  as  in  this  case,  the  two 
ducts  become  a  closed  channel,  the  entrance  of  bile  into 
the  pancreas  or  of  pancreatic  juice  into  the  bile  passages 
would  depend  upon  the  relative  pressure  in  the  two  ducts. 
The  pressure  at  which  bile  and  pancreatic  juice  are 
secreted  being  small,  any  slight  difference  that  might 
exist  would  be  overcome  by  the  gall-bladder,  a  muscular 
organ  which  at  intervals  forces  bile  in  considerable  quan- 
tity along  the  common  duct. 

The  following  case  described  by  Bunting  is  almost 
identical  with  Case  II;  a  small  gall-stone  had  lodged  at 
the  duodenal  orifice  of  an  unusually  capacious  diverticu- 
lum of  Vater  and  the  adjacent  part  of  the  duct  of  Wir- 
sung  was  stained  with  bile. 

Case  Described  by  Bunting.*" — A  man  aged  fifty-one  years  died 
about  twenty-four  hours  after  the  onset  of  intense  epigastric  pain  and 
collapse.  There  was  so-called  acute  hemorrhagic  pancreatitis  with  fat 
necrosis.  The  gall-bladder  was  distended  and  tense  and  the  bile  ducts 
were  dilated.  Gentle  pressure  failed  to  force  bile  from  the  bile  papilla, 
but  increased  pressure  caused  a  sudden  spurt  of  bile,  carrying  with  it 

"Bunting:  Bull,  of  the  Johns  Hopkins  Hosp.,  1906,  xvii,  265. 


140  DISEASE  OF  THE  PANCREAS 

a  small  yellowish-white  mass  which  was  lost  and  not  identified  with  cer- 
tainty. A  small  calculus,  2  mm.  in  diameter,  was  found  at  the  apex  of 
the  diverticulum  of  Vater,  and  in  the  gall-bladder  were  about  four  hun- 
dred light-colored  calculi  from  0.5  to  6  mm.  in  diameter.  The  duct  of 
Wirsung  joined  the  common  bile  duct  11  mm.  from  the  tip  of  the 
papilla;  it  was  dilated  and  stained  with  bile  for  a  distance  4  cm.  from 
its  end. 

Effect  of  Bile  Injected  into  the  Pancreatic  Duct. — Ex- 
periments previously  described  have  shown  that  a  variety 
of  irritating  substances  injected  into  the  pancreatic  duct 
causes  hemorrhagic  necrosis  of  the  gland.  Cases  just 
described  have  demonstrated  in  association  with  this 
lesion  a  mechanism  by  which  a  small  biliary  calculus 
diverts  bile  into  the  pancreatic  duct.  A  series  of  experi- 
ments ^^'  were  undertaken  in  order  to  determine  the  effect 
of  bile  thus  brought  into  contact  with  the  pancreatic 
parenchyma.  The  duodenum  of  dogs  was  opened  for  a 
distance  of  several  centimetres  opposite  the  larger  pan- 
creatic duct.  The  blunt-pointed  nozzle  of  a  syringe  was 
inserted  into  the  orifice  of  the  duct,  and  bile  obtained 
from  the  same  or  from  a  second  dog  was  injected  into  the 
organ.  The  operations  were  performed  with  the  usual 
aseptic  precautions,  and  the  duodenal  wound  was  closed 
by  submucous  mattress  sutures.  The  results  were  almost 
uniform.  Experiments  exhibiting  features  repeated  in 
the  others  will  be  described  in  detail. 

Experiment  I. — After  opening  the  duodenum  of  a  dog,  5  c.c.  of 
bile  obtained  from  a  second  animal  were  injected  into  the  pancreatic 
duct.  Death  followed  within  twenty  hours.  The  peritoneal  cavity 
f'onlains  several  cubic  centimetres  of  bloody  fluid  and  the  peritoneal 

"  Opie :  Bull,  of  the  Johns  Hopkins  Hosp.,  1901,  xii,  182. 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         141 

surface  is  deeply  injected.  The  entire  omentum  and  the  fat  about  the 
pancreas  are  studded  with  conspicuous  opaque  white  areas  of  fat  ne- 
crosis. The  splenic  ai-rn  and  the  upper  half  of  the  attached  duodenal 
part  of  the  pancreas  are  swollen,  oedematous  and  infiltrated  with  blood. 
The  cut  surface  has  a  mottled  dull  red  and  gray  color,  the  interstitial 
tissue  being  hemorrhagic.  Microscopical  examination  shows  that  the 
dull  red  areas  in  the  pancreas  seen  macroscopically  represent  foci  of 
necrosis  where  parenchymatoi;s  cells  stain  only  with  eosin  and  no 
longer  contain  nuclei.  The  blood-vessels  here  are  widely  dilated,  and 
abundant  hemorrhage  has  frequently  taken  place.  Polynuclear  leuco- 
cytes are  present,  but  are  not  very  numerous.  Such  an  area  of  necrosis 
and  hemorrhage  is  at  times  limited  to  the  central  part  of  a  lobule  group, 
while  the  acini  farther  from  the  central  duct  are  intact.  The  interstitial 
tissue,  particularly  in  the  duodenal  part  of  the  gland,  is  oedematous 
and  contains  red  blood-corpuscles,  polynuclear  leucocytes,  and  fibrin. 

Should  bile  enter  the  pancreas  after  occlusion  of  the 
distal  end  of  the  diverticulum  of  Vater,  its  only  opportun- 
ity for  escape  would  be  by  way  of  the  lesser  pancreatic 
duct.  In  order  to  reproduce  this  condition,  in  two  ex- 
periments the  duodenum  was  not  opened,  but  the  duct  was 
exposed  where  it  approaches  the  intestine,  ligated  close 
to  the  duodenum,  and  partially  cut  across.  By  means  of 
a  syringe  with  a  blunt  nozzle  bile  was  injected  into  the 
distal  end  of  the  duct,  which  was  then  ligated. 

Experiment  II. — Into  the  larger  duct  was  injected  5  e.c.  of  bile 
obtained  by  puncture  from  the  dog's  gall-bladder.  The  animal  died 
twenty-four  hours  later.  Opaque,  white  areas  of  fat  necrosis  are 
numerous  upon  the  surface  of  the  pancreas,  in  adjacent  fat,  and  in  the 
omentum.  The  parenchyma  throughout  the  gland  is  mottled  with  small 
dull-red  areas.  Microscopic  examination  shows  the  presence  of  numer- 
ous foci  of  necrosis.  The  gland  cells  have  assumed  a  hyaline  appear- 
ance and  have  lost  their  ni;clei.  The  blood-vessels  in  these  areas  are 
widely  distended,  and  at  times  there  is  abundant  extravasation  of  red 
blood-corpuscles.      Polynuclear  leucocytes  in  moderate  number  are  seen 


142  DISEASE  OF  THE  PANCREAS 

between  the  necrotic  cells.     The  interlobular  tissue  contains  red  blood- 
corpuscles,  polynuclear  leucocytes,  and  fibrin. 

The  injection  of  5  e.c.  of  bile  into  the  pancreatic 
duct  caused  hemorrhagic  inflammation  of  the  gland  with 
fat  necrosis  in  four  dogs,  two  of  which  died  within 
twenty-four  hours  after  the  operation.  Death  did  not 
follow  the  use  of  smaller  amounts,  and  the  changes  pro- 
duced in  the  organ  were  less  wide-spread  and  severe. 

Experiments  of  Flexner  and  Pearce,  of  Hewlett  ^^ 
and  of  Gulecke  have  furnished  additional  evidence  that 
bile  injected  into  the  pancreatic  duct  of  animals  repro- 
duces hemorrhagic  necrosis  of  man.  Flexner  ^^  has 
shown  that  the  power  of  bile  to  cause  the  lesion  is  attribu- 
table to  the  bile  salts ;  five  cubic  centimetres  of  a  solution 
of  sodium  taurocholate  of  strength  approximately  equal 
to  that  of  bile  causes  pancreatic  necrosis  accompanied 
by  wide-spread  fat  necrosis.  The  muciginous  residue 
of  the  bile,  insoluble  in  alcohol,  fails  to  cause  the  same 
change  and  in  common  with  certain  bland  colloids  tends 
to  diminish  the  power  of  bile  salts  to  cause  destruction 
of  pancreatic  parenchyma. 

The  foregoing  experiments  show  that  bile  diverted 
into  the  pancreatic  duct  by  a  biliary  calculus  is  capable 
of  producing  hemorrhagic  necrosis  of  the  pancreas.*^ 

"Hewlett:  Jour,  of  Med.  Res.,  1904,  xi,  377. 

*  Flexner :  Jour,  of  Exper.  Med.,  1906,  viii,  167. 

"It  is  probable  that  the  physiologist,  Claude  Bernard,  produced 
the  lesion,  though  he  failed  to  recog-nize  it,  years  before  it  had  be(en 
described  in  man.  In  his  lectures  on  experimental  physiology,  pub- 
lished in  1856,  he  describes  the  injection  of  a  mixture  of  bile  and  sweet 
oil  into  the  pancreatic  duct  of  the  dog;  the  animal  died  after  eighteen 
hours;  there  was  intense  peritonitis  and  the  pancreas  was  red  and  con- 
tained numerous  eechymoses.  (Lemons  de  physiologie  experimentale, 
Paris,  1856,  ii,  278.) 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         143 

Conditions  Which  Favor  the  Occurrence  of  Hemor- 
rhagic Necrosis  of  the  Pancreas. — A  small  calculus  only 
partially  filling  the  ampulla  of  Vater  can  convert  the  two 
ducts  into  a  continuous  channel,  whereas  a  larger  stone 
may  simultaneously  obstruct  the  duodenal  orifice  of  the 
diverticulum  and  the  orifices  of  the  two  ducts  which  enter 
it,  thus  damming  back  bile  and  pancreatic  juice  upon 
their  respective  glands.  In  Case  II,  as  previously  men- 
tioned, the  diverticulum  measured  10  mm.  in  length,  the 
calculus  3  mm.  in  diameter.  In  many  cases  of  so-called 
hemorrhagic  and  of  hemorrhagic  and  gangrenous  pan- 
creatitis, gaU-stones  found  in  the  gall-bladder  and  bile 
passages  at  autopsy  have  been  small  and  are  often  de- 
scribed as  pea-sized.  This  statement  is  made  in  the 
reports  of  Day,  Cutler,  Kennan,  Simpson,  Chiari^"  (two 
cases),  Smith,'*^  Ehrich,^^  Fraenkel.^''^  Korte.^^  Morian,^- 
Eolleston,^^  Grawitz,  Opie  (Cases  I.  11.  Ill  and  IV). 
Bryant,^*  Lund  ^^   (three  cases)  and  Bunting. 

In  the  two  following  cases  the  bile  passages  were  not 
occluded  but  the  gall-bladder  contained  a  considerable 
number  of  uniformly  smaU  stones  any  one  of  which  might 
have  occluded  the  orifice  of  the  diverticulum  of  Vater 
without  filling  the  cavity  of  the  diverticulum. 

''  Chiari :  Prager  med.  Woch.,  1883,  \in,  285,  297. 

"Smith,  J.  A.:    British  Med.  Jour.,  1897,  ii,  4SS. 

^''Ehrich:  Beit.  z.  klin.  Chir..  1S9S,  xx,  315. 

"Traenkel:  Miinchener  med.  Woc-h..  1S96.  xliii.  813.  844. 

'^  Korte :  Areh.  f .  klin.  Chir..  1894,  xlviii,  721. 

"^  Morian :  Miinchener  med.  "VToch.,  1899,  xlri.  348. 

'"Rolleston:  Trans,  of  the  Path.  Soe.  of  London.  1893.  xliv.  71. 

"  Bryant :  Lancet,  1900,  ii,  1341. 

"  Lnnd :  Boston  Med.  and  Surc.  Jour..  1900.  cxliii.  543. 


144  DISEASE  OF  THE  PANCREAS 

Case  III. — A  man,  aged  thirty-seven  years,  was  admitted  to  the 
Johns  Hopkins  Hospital  in  the  care  of  Dr.  Halsted.  An  attack  of 
epigastric  pain  with  vomiting  had  oecniTed  seven  months  before.  The 
present  similar  attack  began  fourteen  days  before  admission. 

There  was  swelling  in  the  region  of  the  gall-bladder,  but  no  jaun- 
dice; ill-defined  mass  was  felt  in  the  epigastric  region.  An  exploratoiy 
laparotomy  was  perfonned.  Leucocytes  found  to  number  33,700;  tem- 
perature was  101°  to  104°  F.  Death  occun'ed  four  days  after  admis- 
sion. The  lesser  peritoneal  cavity  was  transformed  into  a  cavity 
containing  bloody  fluid  and  necrotic  material;  there  were  perfora- 
tions into  the  transvei-se  colon,  stomach  and  duodenum.  The  body 
and  tail  of  the  pancreas  was  necrotic  and  in  places  infiltrated  with  blood. 
The  diverticulum  of  Vater  was  10  mm.  in  length.  The  gall-bladder 
contained  nine  faceted  gall-stones,  the  largest  being  5  mm.  in  diameter. 

Case  IV."^" — M.  K.  female,  aged  thirty-four  years,  was  admitted 
to  the  Presbyterian  Hospital  of  New  York  in  the  service  of  Dr.  Eliot 
on  November  8,  1908. 

Present  Illness. — In  February,  1908,  the  patient  was  suddenly 
attacked  with  severe  pain  in  the  epigastrium.  There  was  slight  jaundice. 
Symptoms  continued  for  about  three  weeks,  and  disappeared.  About 
October  1,  1908,  she  was  again  attacked  with  severe,  sharp,  epigastric 
pain  accompanied  by  vomiting,  but  no  jaundice.  About  the  middle 
of  October  the  pain  gi-adually  diminished  and  almost  disappeared. 
October  24,  1908,  she  had  a  severe  chill  followed  by  sweating. 

On  entrance  to  the  hospital  the  patient  was  well  nouiished  but  very 
pale;  there  was  no  jaundice.  In  the  epigastrium  to  the  right  of  the 
midline  was  a  fluctuating,  slightly  tender  mass,  8  cm.  in  diameter. 

On  November  9,  1908,  Dr.  Eliot  opened  the  abdomen  and  evacuated 
a  large  abscess  apparently  connected  with  the  liver.  It  contained  a 
large  quantity  of  thick,  brownish  pus,  with  vei-y  little  odor.  Agar-agar 
inoculated  with  this  pus  remained  sterile.  After  operation  the  patient 
did  not  improve  and  vomited  frequently. 

On  November  30, 1908,  a  second  operation  was  performed.     A  large 

■^  This  case  and  Cases  VI  and  VII  have  been  described  by  Opie 
and  Meakins :  Jour,  of  Exper.  Med.,  1909,  xi,  561. 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         145 

cavity  was  found  extending  to  the  posterior  parietes  and  for  some  dis- 
tance both  to  the  right  and  to  the  left  of  the  midline.  The  patient  did 
not  improve  after  the  second  operation  and  died  December  1,  1908. 

Temperature  after  admission  to  the  hospital  ranged  from  100  to 
104°  r.  Urine  contained  no  bile  or  sugar;  the  pancreatic  reaction  of 
Cam  midge  was  negative. 

The  white  blood-corpuscles  on  entrance  to  the  hospital  numbered 
14,800,  but  diminished  to  3000  per  mm.  ProgTessive  diminution 
of  polynuclear  leucocytes  with  increase  of  transitional  forms,  large 
mononuclear  leucocytes  and  lymphocytes  is  exhibited  by  the  following 
counts : 

Nov.  8       Nov.  16      Nov.  18      Nov.  25    Nov.  28    Nov.  30 

Total  leucocytes    ...  14,800  10,700     15,700     4,800  2,750  3,000 

Poly,  leucocytes   78.5%  77%  29%  26%  41.5% 

Transitional  6  6  16  27.5  15 

Large  mononuclears  ....  2  2  21            4  16 

Lymphocytes    13  14.5  31  42  25.5 

Basophilic   leucocytes    . .  0  0  0           0  0.5 

Eosinophile  leucocytes  . .  0  0  11  .15 

Stimulation  forms   0.5  0.5  2           0  0 

Autopsy. — In  the  upi^er  right  hypochondrium  from  the  wound  of 
operation  there  is  a  deep  sinus  surrounded  by  firm  adhesions. 

In  the  fat  of  the  omentum  over  the  transverse  colon  and  at  the 
base  of  the  mesenteiy  there  are  numerous  small,  white  areas  of  fat 
necrosis.  From  the  opening  in  the  abdominal  wall  the  sinus  with 
necrotic  edges  passes  directly  backward  to  the  duodenum.  It  com- 
municates with  a  very  large  cavity  lying  in  front  of  the  pancreas  and 
representing  in  part  the  lesser  peritoneal  cavity.  An  extension  from 
this  cavity  passes  downward  into  the  retroperitoneal  tissues  to  the  left 
of  the  root  of  the  mesentery,  and  in  front  of  the  kidliey.  Erosion  in 
this  region  has  extended  into  the  abdominal  wall  and  has  reached  to 
within  about  1  cm.  of  the  surface  above  the  crest  of  the  ilium. 

Behind  the  body  of  the  pancreas,  extending  upward  through  the 

retroperitoneal  tissue  is   a  second  sinus  which  communicates  with  an 

immense  cavity  above  the  stomach  and  immediatelj^  below  the  diaphragm. 

The  diaphragm  to  the  left  of  the  midline  in  contact  with  the  abscess 

10 


146  DISEASE  OF  THE  PANCREAS 

cavity  is  penetrated  by  an  opening  1.5  on.  across.  This  opening  com- 
municates with  a  localized  pleural  abscess  (7  by  8  cm.)  about  which 
the  lung  is  firmly  bound  to  the  diaphragm. 

In  front  of  the  head  of  the  pancreas  is  the  abscess  cavity  de- 
scribed above;  the  surface  of  the  gland  is  here  covered  by  soft,  black 
tissue.  This  black  gangrenous  tissue  covers  the  body  of  the  pancreas 
half  way  to  the  splenic  extremity,  whereas  the  remainder  of  the  anterior 
surface  of  the  body  and  tail  is  adherent  to  the  stomach  and  shows 
neither  necrosis  nor  erosion.  The  abscess  cavity,  which  has  burrowed 
underneath  the  gland  about  its  midpart,  dissects  the  greater  part  of  the 
posterior  surface  of  the  splenic  half  from  the  imderlying  retroperi- 
toneal tissue.  The  pancreas  throughout  is  finn  and  on  section  the 
lobulation  is  less  clearly  defined  .than  usual.  On  the  surface  and  less 
frequently  in  the  substance  of  the  gland  occur  opaque,  yellow  spots  of 
fat  necrosis.  On  section  through  the  abscess  wall  into  the  head  of  the 
pancreas  a  narrow  zone  of  fibrous  tissue  is  found  between  the  necrotic 
abscess  wall  and  the  pancreatic  parenchyma.  The  duct  of  the  pancreas 
is  slightly  dilated  and  patulous.  The  common  bile  duet  is  somewhat 
dilated  and,  1  cm.  above  the  orifice,  measures  16  mm.  in  circumference. 
The  duct  of  Wirsung  joins  the  common  bile  duet  7  mm.  from  its 
duodenal  orifice  which  measures  3  mm,  in  diameter. 

The  gall-bladder  contains  eleven  small  gall-stones  measuring  from 
6  to  9  mm.  in  diameter  (Fig.  21).  The  cystic  duet  is  dilated.  The 
stomach  and  duodenum  are  apparently  normal. 

Culture  from  the  peritoneum  contains  many  varieties  of  bacteria, 
including  streptococci  and  B.  coli,  together  with  unidentified  bacteria. 

Microscopic  examination  shows  that  the  capsule  of  the  pancreas 
is  much  thickened.  Its  outer  layer  is  necrotic  and  the  inner  layer 
consists  of  vascular  granulation  tissue  in  which  are  hemorrhages.  Ex- 
tending in  from  the  capsule  are  greatly  thickened  strands  and  masses 
of  similar  tissue  in  which  there  are  numerous  round  cells.  In  large 
areas  parenchyma  is  almost  wholly  replaced  and  lobules  are  represented 
by  a  few  acini. 

Anatomical  Diagnosis. — HeKiDrrhagic  necrosis  o^  the  pancreas  in 
process  of  healing;  disseminated  fat  necrosis;  peripancreatie  abseess 
with  erosion  of  retroperitoneal  tissue;  subdiaphragmatic  abseess;  per- 


Fig.  21. — Gall-stones  from  Case  IV. 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         147 

f oration  of  the  diaphragm;  localized  diaphragmatic  empyema;  pneumo- 
thorax. Cholelithiasis;  chronic  cholangitis;  fatty  degeneration  of  the 
liver.     Bronchopneumonia.     Fibromyoma  of  the  uterus. 

Anatomical  peculiarities  of  the  diverticulum  of  Vater 
favor  or  prevent  conversion  of  the  two  ducts  into  a  closed 
channel.  The  diverticulum  may  be  regarded  as  a  some- 
what conical  cavity  into  the  base  of  which  open  the  bile 
and  pancreatic  ducts ;  the  apex  of  the  cone  situated  at  the 
summit  of  the  bile  papilla  is  the  common  duodenal  orifice 
of  both  ducts.  In  a  considerable  number  of  individuals, 
about  one  in  ten  (see  page  15)  the  two  ducts  open  sepa- 
rately into  the  intestine  and  no  diverticulum  exists  (see 
Fig.  9,  ii.).  Variations  to  which  the  diverticulum  is 
subject  have  been  considered  (page  15  et  seq.) ;  in  one 
hundred  instances  its  length  varied  from  zero  to  11  mm., 
and  in  only  thirty  of  these  did  the  length  reach  5  nam. 
The  average  diameter  of  the  duodenal  orifice  was  2.5 
mm.  and  in  about  one-third  of  the  subjects  examined  the 
diameter  of  the  orifice  was  equal  or  greater  than  the 
length  of  the  diverticulum.  If  possible  distention  of  the 
orifice  be  considered,  it  is  hardly  probable  that  a  small 
calculus  could  lodge  in  the  opening,  yet  only  partially  fill 
the  cavity,  unless  the  length  of  the  diverticulum  should 
exceed  the  diameter  of  the  orifice  by  several  millimetres. 
Since  in  only  thirty-two  of  one  hundred  instances  does 
the  length  of  the  diverticulum  exceed  5  mm.,  the  average 
diameter  of  the  orifice  being  2.5  mm.,  it  is  probable  that 
in  little  more  than  three  of  ten  individuals  are  the  ana- 
tomical conditions  such  that  a  small  calculus  might  divert 
the  bile  into  tlft  pancreatic  duct.  Moreover,  it  must  be 
remembered,  in  one  of  ten  cases  the  bile  duct  joins  the 
smaller  pancreatic  duct,  while  the  larger  duct  of  Santo- 


148  DISEASE  OF  THE  PANCREAS 

rini  enters  the  duodenum  at  the  site  of  the  lesser  papilla. 
These  facts  explain  in  part  the  rarity  of  hemorrhagic 
necrosis  of  the  pancreas  when  compared  with  the  relative 
frequency  of  cholelithiasis. 

Frequency  with  which  Hemorrhagic  Necrosis  of  the 
Pancreas  is  Produced  by  Biliary  Calculi. — While  the  eti- 
ology of  many  cases  of  hemorrhagic  pancreatitis  is  thus 
established,  it  cannot  be  demonstrated  that  all  are  depen- 
dent upon  the  passage  of  a  gall-stone  along  the  common 
bile  duct.  In  the  following  case  neither  the  clinical  his- 
tory nor  the  autopsy  affords  any  evidence  of  cholelithi- 
asis. A  complete  autopsy  was  not  permitted,  and  the 
possibility  cannot  be  excluded  that  a  single  small  cal- 
culus producing  the  lesion  escaped  into  the  intestine. 

Case  V. — The  patient,  a  man,  twenty-eight  years  of  age,  had, 
been  in  good  health  before  his  illness,  which  began  four  days  before 
death  with  nausea  and  vomiting.  About  an  hour  later  he  was  attacked 
with  agonizing  pain  in  the  epigastric  region.  The  following  day  he 
suffered  with  violent  hiccough,  which  continued  until  the  time  of  opera- 
tion. When  admitted  to  the  Johns  Hopkins  Hospital  he  vomited 
almost  continuously;  there  was  distention  in  the  neighborhood  of  the 
umbilicus.  An  exploratory  laparotomy  was  perforaied  by  Dr.  J.  F. 
Mitchell,  and  innumerable  foci  of  fat  necrosis  were  found  studding 
the  omentum.  Lesser  peritoneal  cavity  contained  bloody  fluid,  and 
the  pancreas  was  covered  by  a  coagulum  of  blood.  The  abdomen  was 
closed,  a  gauze  drain  being  inserted  into  the  wound.  The  patient 
died  twenty-four  hours  later. 

Autopsy. — It  was  possible  to  remove  only  the  pancreas  with  the 
gall-bladder  and  a  part  of  the  duodenum.  The  pancreas  was  of  great 
size,  weighing  190  Gm. ;  the  head  and  tail  were  firm  and  normal  in 
appearance,  but  the  greater  part  of  the  body  was  soft,  mottled  red  and 
reddish-black,  and  was  the  seat  of  a  hemorrhagic  lesion.  No  gall- 
stones were  found  in  the  gall-l)ladder  or  in  the  gall-duct.     Parenchyma 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         149 

had  undergone  necrosis  and  neigliboring  interstitial  tissue  was  infiltrated 
with  red  blood-cori^uscles,  leucocytes  and  fibrin.  There  is  hyaline 
thrombosis  of  capillai-y  vessels  at  the  margin  of  necrotic  tissue. 

A  case  described  by  Pearce  ^"  illustrates  the  possibil- 
ity that  the  bile  passages  may  have  contained  a  single 
gall-stone  which  has  been  lost  in  the  intestinal  contents. 
Hemorrhagic  pancreatitis  (necrosis)  was  found  in  an 
individual  who  had  been  jaundiced  two  weeks  before 
death;  no  calculi  were  found  at  autopsy  but  the  orifice 
of  the  common  bile  duct  was  dilated  and  just  above  the 
orifice  there  was  localized  dilatation  which  suggested  that 
a  stone  had  occupied  the  end  of  the  duct.  In  an  almost 
identical  case  described  by  Thayer  (see  page  33)  a  gall- 
stone was  found  in  the  duodenum. 

It  has  been  claimed  that  gall-stones  are  not  more  fre- 
quently found  in  association  with  acute  hemorrhagic 
pancreatitis  than  in  individuals  of  similar  age  dying 
from  other  diseases.  Among  eight  cases  of  hemorrhagic 
necrosis  (acute  hemorrhagic  pancreatitis),  which  I  have 
had  the  opportunity  of  studying,  gall-stones  have  been 
present  in  five.  Among  one  hundred  and  five  recorded 
cases  collected  by  Egdahl,  cholelithiasis  was  present  in 
42  per  cent.  This  proportion,  which  may  be  regarded 
as  an  established  minimum,  is  doubtless  small,  for  in 
many  instances  data  which  have  been  recorded  do  not 
exclude  the  presence  of  gall-stones.  Their  presence  may 
have  been  overlooked  or  a  single  calculus  causing  the 
lesion  has  perhaps  been  lost.  iVccording  to  the  statistics 
collected  by  Korte,  acute  hemorrhagic  and  gangrenous 
pancreatitis  occurs  with  few  exceptions  between  the  ages 

''  Pearce :  Albany  Med.  Ann.,  1904,  sxv,  389. 


150  DISEASE  OF  THE  PANCREAS 

of  twenty  and  sixty  years.  According  to  statistics  of 
Mosher,^^  carefully  compiled  from  German  and  American 
sources,  the  frequency  of  gall-stones  between  the  ages  of 
twenty-one  and  sixty  years  is  represented  by  8.9  per  cent, 
of  all  autopsies,  less  than  one-fourth  of  the  proportion 
found  with  the  acute  pancreatic  lesion. 

The  somewhat  greater  frequency  of  pancreatic  ne- 
crosis in  men,  whereas  gall-stones  are  more  common  in 
women,  is  perhaps  referable  to  the  greater  ability  of  the 
gall-bladder  in  stout  muscular  men  to  drive  bile  from 
the  gall-bladder  into  the  pancreatic  ducts  during  the 
passage  of  a  gall-stone  from  the  diverticulum  of  Vater 
into  the  duodenum. 

Hemorrhagic  Necrosis  Caused  by  Penetration  of 
Duodenal  Contents  into  the  Pancreatic  Ducts. — In  many 
cases  of  so-called  acute  pancreatitis  there  have  been 
symptoms  referable  to  the  stomach  or  intestine,  but  the 
etiological  relation  of  gastro-intestinal  disturbance 
(noted  in  thirty- two  of  one  hundred  and  five  cases  col- 
lected by  Egdahl)  is  doubtful,  for  symptoms  referred 
to  the  stomach  may  be  caused  by  cholelithiasis  and  in- 
flammation of  the  duodenum  is  frequently  secondary  to 
the  adjacent  pancreatic  lesion. 

The  power  of  duodenal  contents  to  cause  hemorrhagic 
necrosis  of  the  pancreas  has  been  repeatedly  shown  by 
experiments.  Hlava,  who  showed  that  acid  gastric  con- 
tents injected  into  the  pancreatic  duct  causes  the  lesion, 
has  suggested  that  antiperistaltic  movements  of  the  in- 
testine might  drive  gastric  or  duodenal  contents  into  the 
pancreatic  ducts;  there  is  no  evidence  that  the  lesion  is 

"Mosher:    Bull,  of  the  Johns  Hopkins  Hosp.,  1901,  xii,  253. 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         151 

produced  in  this  way.  The  discovery  of  enterokinase 
in  the  intestinal  juice  has  suggested  that  self-digestion 
of  the  pancreas  might  occur  during  life  should  entero- 
kinase find  its  way  into  the  pancreas.  The  part  played 
by  enterokinase  is  somewhat  doubtful  (Polya,  Williams 
and  Busch),  but  several  experimenters  (Polya,  Hess^^) 
have  shown  that  small  quantities  of  duodenal  contents 


D.W. 


Fig.  22. — Diagram  showing  the  usual  relative  size  of  the  duct  of  Wirsung  (D.W.)  and  duct 
of  Santorini  (D.S.)  ;  the  duct  of  Wirsung  joins  the  common  bile  duct  (D.C.) . 

injected  into  the  pancreatic  duct  will  produce  acute  pan- 
creatic necrosis  with  fat  necrosis. 

Hess  attempted  to  produce  pancreatic  necrosis  by 
diverting  intestinal  contents  into  the  pancreatic  ducts; 
he  fixed  in  the  duodenal  orifice  of  the  pancreatic  duct  of 
the  dog  a  small  cannula  with  a  funnel-shaped  end  project- 
ing into  the  duodenum  and  caused  stenosis  of  the  duode- 
num by  a  ligature  below  the  pancreas.     Olive  oil  injected 


Hess:    Miinchener  med.  Woeh.,  1905,  Hi,  644. 


152 


DISEASE  OF  THE  PANCREAS 


into  the  duodenum,  Hess  thought,  favored  the  production 
of  the  lesion.  In  one  of  three  experiments  there  was 
hemorrhagic  necrosis  of  the  pancreas,  with  disseminated 
fat  necrosis,  and  death  occurred  at  the  end  of  two  days. 
Hess  cited  cases  of  Gerhardi  and  of  Konig-Werth  in 
which  with  acute  hemorrhagic  pancreatitis  there  was 
stenosis  of  the  duodenum  below  the  pancreas. 


Fig.  23. — Diagram  showing  the  relative  size  of  the  two  pancreatic  ducts  in  Case  VI. 
The  part  of  the  gland  drained  by  the  duct  of  Santorini  is  indicated  in  both  diagrams  by 
curved  lines. 

It  is  well  known  that  increased  pressure  within  the 
duodenum  does  not  force  duodenal  contents  into  the  bile 
duct  or  into  the  pancreatic  duct  after  death.  The  deli- 
cate valves  found  within  the  diverticulum  of  Vater  pre- 
vent regurgitation.  In  approximately  one  of  ten  individ- 
uals (see  page  10)  what  is  usually  the  accessory  duct 
of  the  pancreas — namely,  the  duct  of  Santorini,  is  the 
chief  outlet  of  the  gland  and  is  larger  than  the  duct  of 
Wirsung  which  joins  the  common  bile  duct   (Fig.  23). 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         153 

The  orifice  of  such  an  anomalous  duct  is  perhaps  unable 
to  prevent  regurgitation  of  intestinal  contents  when  pres- 
sure within  the  duodenum  is  increased  by  vomiting.  In 
the  following  case  this  anomaly  exists  and  perhaps  ex- 
plains the  occurrence  of  the  pancreatic  lesion. 

Case  VI. — J.  S.  was  admitted  to  the  service  of  Dr.  Eliot  in  the 
Presbyterian  Hospital  on  October  25,  1908.  The  patient,  male,  aged 
fifty-five  years,  had  used  alcohol  in  excess;  in  October,  1906,  he  had 
acute  alcoholic  gastritis  and  suffered  with  frequent  vomiting  and  severe 
diarrhoea;  there  was  no  jaundice.  After  this  iUness  symptoms  of 
chronic  gastritis  continued  and  there  was  frequent  vomiting  and  eruc- 
tation. On  October  22,  1908,  there  was  sudden  severe  epigastrio  pain 
followed  by  vomiting.  The  pain  continued  to  be  severe  and  extended 
a  little  outside  the  epigastric  region.  Vomiting  was  almost  continuous; 
there  was  constipation. 

On  entrance  to  the  Hospital  the  patient  was  almost  moribund; 
the  face  and  hands  were  cyanotic;  there  was  no  jaundice.  Tempera- 
ture was  99.6°  F. ;  respiration,  40;  pulse,  140.  The  abdomen  was 
symmetrical  and  distended  but  not  very  tense;  it  moved  little  with 
respirations.  There  was  tenderness  and  rigidity  in  the  right  upper 
quadrant  and  in  less  degree  in  the  left  upper  quadrant.  No  mass  was 
palpable. 

No  urine  was  obtainable  for  examination. 

White  blood-corpuscles,  Oct.  25,  numbered  9900  per  mm.  Differ- 
ential count :  polymorphonuclear  leucocytes,  88  per  cent. ;  transitionals,  5 
per  cent.;  large  mononuclear  leucocytes,  1  per  cent.;  lymphocytes,  5 
per  cent.,  and  eosinophiles  0.5  per  cent. 

Patient  died  six  hours  after  entrance  to  the  Hospital. 

Autopsy. — The  mesentery  is  studded  with  small  areas  of  fat 
necrosis,  most  numerous  on  the  right  side,  and  many  large  foci  are 
found  in  the  perirenal  fat. 

The  tail  and  body  of  the  pancreas  are  soft  and  in  great  part  dark 
red,  being  mottled  with  lighter,  gi-ayish  areas.  Here  and  there  occur 
minute  white  spots  of  fat  necrosis.  Upon  the  surface  of  the  body 
occur  a  few  black  spots  extending  into  the  substance  of  the  gland; 


154  DISEASE  OF  THE  PANCREAS 

they  represent  the  only  evidence  of  hemoiThage.  The  greater  part  of 
the  head  of  the  gland  shows  the  same  changes  and  one  or  two  black 
spots  occur;  the  only  part  of  the  gland  which  has  the  appearance  of 
normal  tissue  is  situated  on  the  posterior  and  lowei^  part  of  the  head 
in  contact  with  the  duct  of  Wirsung. 

Th6  gall-bladder,  which  measures  11  by  5  cm.,  is  distended  with 
rather  thick,  dai'k  gi-een  bile,  and  contains  no  stones  or  sand.  The 
bile  ducts  are  patent.  Stomach  is  large;  its  mucous  membrane  is  in 
places  injected  and  covered  by  blackish  mucus.  The  duodenum  is 
normal. 

Cultures  from  spleen  and  liver  contain  Bacillus  coli;  aerobic 
and  anaerobic  cultures  from  the  pancreas  contain  only  Bacillus  coli. 

Microscopic  Examination  of  the  Pancreas. — A  section  from  the 
head  near  the  duct  of  Santorini  shows  necrosis  and  disintegration  so 
that  the  architecture  of!  the  gland  is  completely  lost.  In  a  few  small 
spots  parenchyma  is  well  preserved,  acini  being  intact  and  nuclei  well 
stained.  Here  interstitial  tissue  is  distended  as  if  by  oedema,  red  blood- 
corpuscles  are  fairly  numerous  and  polynuclear  leucocytes  occur  in 
small  number.  About  the  duct  of  Wirsung  there  is  in  places  necrosis 
with  loss  of  nuclei,  but  except  in  a  few  areas  the  shape  of  the  acini  is 
recognizable,  whereas  in  the  greater  part  of  the  section  tissue  is  intact 
and  nuclei  are  stained.  A  section  from  the  body  shows  almost  com- 
plete disintegration  similar  to  that  about  the  duct  of  Santorini.  In  an 
area  of  intact  tissue  there  is  considerable  increase  of  connective  tissue 
in  great  part  about  the  lobules ;  this  tissue  contains  numerous  lymphoid 
cells  and  red  blood-corpuscles  and  a  few  polynuclear  leucocytes.  Tissue 
in  the  tail  of  the  gland  is  in  part  necrotic  and  disintegrated,  in  part 
living.  The  preserved  tissue  is  in  places  infiltrated  with  red  blood- 
corpuscles.  Well-preserved  islands  of  Langerhans  occur  in  fair  abund- 
ance.    Small  veins  contain  thrombi. 

Anatomical  Diagnosis. — Hemorrhagic  necrosis  of  the  pancreas; 
chronic  interstitial  pancreatitis;  fat  necrosis;  chronic  pulmonary  tuber- 
culosis; chronic  interstitial  nephritis;  fatty  degeneration  of  the  liver; 
arteriosclerosis. 

The  ducts  of  the  pancreas  exhibit  an  anomalous, 
arrangement.    The  duct  of  Wirsung,  which  joins  the  com- 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         155 

mon  bile  duct,  is  of  small  size  and  drains  only  a  small 
part  of  the  head  of  the  gland;  this  area  appears  to  be 
the  least  changed  part  of  the  organ.  The  duct  of  San- 
torini  is  the  chief  outlet  of  the  gland,  and,  far  larger  than 
the  duct  of  Wirsung,  traverses  the  entire  length  of  the 
pancreas  (see  Fig.  23).  The  orifice  of  this  duct  readily 
admits  a  probe  about  2  mm.  in  diameter.  The  gall- 
bladder and  bile  passages  contain  no  calculi. 

Since  the  duct  of  Wirsung  is  relatively  small,  whereas 
the  main  duct  of  the  gland  enters  the  duodenum  about  1.5 
cm.  from  the  common  bile  duct,  bile  could  enter  only  a 
small  part  of  the  pancreas.  On  the  other  hand,  it  is 
not  improbable  that  an  anomalous  duct  opening  by  a  rela- 
tively wide  orifice,  might  have  been  the  portal  of  entry 
for  material  from  the  duodenum. 

Cases  recorded  in  the  literature  of  the  subject  give  some  support 
to  this  view.  Johnstone  '^°  has  described  two  eases  of  acute  pancreatitis 
in  which  the)  pancreatic  ducb  has  opened  into  the  duodenum  1  or  2  cm. 
from  the  common  bile  duct,  and  although  he  has  described  these  cases 
with  the  purpose  of  showing  that  gall-stones  have  not  been  an  etiological 
factor  in  the  production  of  the  lesion,  he  does  not  suggest  that  the 
anomalous  condition  may  explain  its  occurrence.  The  description  of 
this  author  makes  it  probable  that  the  arrangement  of  the  ducts  in  these 
two  cases  resembles  that  which  I  have  just  described.  In  an  additional 
ease  described  by  the  same  author  the  distribution  of  the  ducts  is  not 
described,  whereas  in  a  fourth  case  the  nature  of  the  pancreatic  lesion 
is  doubt  fill. 

Further  evidence  that  the  duct  of  Santorini  may  be  a  portal  of 
entry  for  irritant  material  from  the  duodenmn  is  furnished  by  a  case 
of  Bassett.^     The  two  ducts  of  the  gland  bore  the  usual  relation  to 

""Johnstone:    Colorado  Med.,  1907,  iv,  93. 

"  Bassett :    Trans,  of  the  Chicago  Path.  Soc,  1907,  vii,  83. 


156  DISEASE  OF  THE  PANCREAS 

one  another  (Fig.  22) ;  the  duct  of  Santorini  was  much  smaller  than 
the  duct  of  Wirsung  and  drained  only  a  small  part  of  the  gland. 
This  duct  terminated  at  the  margin  of  an  anomalous  duodenal  diver- 
ticulum of  which  the  mucosa  was  inflamed.  Limited  to  the  immediate 
neighborhood  of  this  small  duct  was  hemorrhagic  pancreatitis  with  fat 
necrosis.  The  patency  of  the  orifice  of  the  duct  of  Santorini  was  not 
demonstrated.  In  Case  VI,  described  above,  almost  the  entire 
gland,  of  which  the  chief  outlet  was  the  duct  of  Santorini,  was  the 
seat  of  hemorrhagic  inflammation,  and  the  part  about  the  small  duet  of 
Wirsung  was  apparently  the  least  changed  part  of  the  organ,  whereas 
in  the  case  of  Bassett,  with  a  small  duct  of  Santorini  terminating  in  an 
anomalous  diverticulum,  the  lesion  was  limited  to  the  small  area  drained 
by  this  duct.  (The  domain  of  the  duct  of  Santorini  in  the  usual  and 
in  the  anomalous  condition  is  indicated  in  Figs.  22  and  23.)  Although 
these  cases  do  not  afford  conclusive  proof  that  duodenal  contents  cause 
the  lesion,  they  suggest  this  possibility  with  such  force  that  a  careful 
study  of  the  topography  of  the  ducts  in  cases  of  hemorrhagic  necrosis 
of  the  pancreas  is  desirable. 

Traumatic  Necrosis  of  the  Pancreas. — Typical  in- 
stances of  the  lesion  usually  designated  acute  hemor 
rhagic  pancreatitis  and  characterized  by  necrosis  of  the 
pancreatic  parenchyma,  hemorrhage,  and  disseminated 
fat  necrosis,  have  followed  abdominal  injury  in  the  epi- 
gastric region.  In  such  cases  there  has  been  a  blow  or 
kick  over  the  pancreas,  perhaps  without  injury  to  the 
skin,  crushing  between  the  buffers  of  two  cars,  etc. 

A  typical  case  is  described  by  Selberg.^^  j^  man  was 
kicked  over  the  stomach  by  a  horse  and  was  unconscious 
for  a  time.  There  was  pain  and  gradual  distention  in  the 
epigastric  region,  together  with  vomiting.  Death 
occurred  after  twenty  days.  The  omentum  was  studded 
with  foci  of  fat  necrosis;  the  pancreas  was  infiltrated 


"Selbcrg:  Berliner  klin.  Woch.,  1901,  xxxviii,  923. 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         157 

with  blood  and  was  gangrenous  in  appearance.  In  the 
following  case  localized  hemorrhagic  necrosis  of  the  pan- 
creas with  localized  fat  necrosis  followed  a  stab  wound 
of  the  abdomen. 

Case  VII. — J.  T.,  male,  aged  20  years,  was  stabbed  on  the  after- 
noon of  November  4,  1908,  in  the  upper  left  quadrant  of  the  abdomen 
with  a  long  stiletto.  After  about  ten  minutes  there  was  vomiting  and 
nausea. 

On  entrance  to  the  Presbyterian  Hospital  a  short  time  after  the 
injury  the  temperature  was  100.6°;  pulse,  96;  respirations,  16.  Just 
above  the  costal  margin  in  the  left  mammillary  line  there  was  a 
horizontal  stab  wound  one  inch  long  and  parallel  to  the  ribs;  through 
the  wound  projected  a  mass  of  omentum,  about  the  size  of  an  egg. 

Exploratory  operation  was  performed  November  4,  1908.  The  stab 
wound  in  the  left  costal  space  perforated  the  diaphragm,  but  the 
pleura  was  not  injured.  Upon  the  anterolateral  surface  of  the  stomach 
was  a  perforation  1.5  cm.  long  through  which  a  small  amount  of  fluid 
had  escaped.  The  posterior  wall  was  apparently  normal.  The  peri- 
toneal cavity  contained  a  large  amount  of  fluid  and  clotted  blood.  The 
intestines  and  other  viscera  were  apparently  uninjured.  The  perfora- 
tion in  the  anterior  waU  of  the  stomach  was  closed  by  sutures. 

During  the  succeeding  days  the  temperature  varied  between  101° 
and  106°,  and  the  pulse  was  rapid.  There  were  frequent  nausea  and 
vomiting.  There  was  distention  of  the  abdomen,  although  the  bowels 
moved  freely  and  considerable  flatus  was  expelled.  Discharge  from  the 
wound  was  profuse.  The  patient  gradually  became  weaker  and  died 
November  9. 

Streptococci  in  pure  cultures  were  found  in  the  peritoneal  exudate 
removed  at  operation.     A  blood  culture  remained  sterile. 

White  blood-corpuscles  numbered  from  3000  to  7000  per  mm. 

Autopsy  was  performed  by  Dr.  Otto  Schultz.  Throughout  the 
peritoneal  cavity  is  fibrinopurulent  exudate.  The  wound  of  the 
anterolateral  wall  of  the  stomach  has  remained  closed  and  is  in 
process  of  healing.  Thew  is  no  perforation  of  the  posterior  wall 
of    the   stomach,    but    opposite    to    the    wound    in    the    anterior    wall 


158  DISEASE  OF  THE  PANCREAS 

there  is  upon  the  mucosa  of  the  posterior  wall  a  circular  spot  of  oedema 
and  injection  2.5  cm.  in  diameter;  a  minute  central  area  of  necrosis 
about  the  size  of  a  pin's  head,j  evidently  represents  the  spot  in  which 
the  point  of  the  knife  has  struck.  Upon  the  surface  of  the  pancreas 
immediately  behind  this  wound  is  a  localized  hemorrhagic  area  about 
3.5  cm.  in  diameter  and  in  the  fat  of  this  area  are  conspicuous  foci 
of  fat  necrosis.     Otherwise  the  pancreas  appears  normal. 

Microscopic  examination  of  the  hemorrhagic  area  in  the  pancreas 
shows  hyaline  necrosis  of  the  pancreatic  parenchyma  similar  to  that 
frequently  obsen-ed  with  so-called  acute  hemorrhagic  pancreatitis;  the 
interstitial  tissue  is  infiltrated  with  blood  and  in  places  contains  poly- 
nuclear  leucocytes.  The  veins  within  the  hemoiThagic  zone  are  widely 
dilated  and  contain  thrombi. 

It  is  noteworthy  that  simple  injury  to  the  pancreas  of 
animals  fails  to  produce  necrosis,  whereas  in  experiments 
of  Levin  ^^  crushing  of  the  gland  associated  with  occlus- 
ion of  blood-vessels  has  been  followed  by  changes  which 
resemble  those  of  hemorrhagic  necrosis.  Trivial  injury 
to  the  pancreas  is  usually  followed  by  rapid  healing  but 
in  Case  YIl  injury  has  been  associated  with  pancreatic 
necrosis,  hemorrhage  and  focal  fat  necrosis.  It  is  not 
improbable  that  the  simultaneous  occurrence  of  localized 
venous  thrombosis  and  pancreatic  injury,  both  due  to 
a  stab  wound,  explains  the  occurrence  of  hemorrhagic 
necrosis  of  pancreatic  parenchyma. 

PATHOLOGY. 

The  appearance  of  the  pancreas  varies  with  the  dura- 
tion of  the  disease,  and  in  accordance  with  the  aspect  of 
the  gland  the  lesion  has  been  described  as  hemorrhagic 
or  as  gangrenous.    AVlien  death  has  occurred  within  a 

"  Levin :  Jour,  of  Med.  Res.,  1907,  xvi,  419. 


£^j. 


'^^C^ 


■  %iU,V-^/ 


^^^" 


Fig.  24. — Hemorrhagic  necrosis  of  the  pancreas  showing  abrupt  transition  from  norma 
to  necrotic  tissue.  At  the  margin  of  the  living  tissue  are  red  blood-corpuscles,  leucocytes, 
and  fibrin. 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         159 

few  days  after  onset  of  symptoms  the  organ  is  much 
enlarged,  and  very  firm,  and  usually  covered  by  clotted 
blood  which  has  assumed  a  blackish-red  color.  The  lesser 
peritoneal  cavity  contains  blood-stained  fluid  and  the  tis- 
sues about  the  pancreas  are  often  infiltrated  with  blood. 
Fat  necrosis  always  accompanies  hemorrhagic  necrosis  of 
the  pancreas.  The  entire  substance  of  the  organ  is 
rarely  affected  by  the  lesion,  and  sharply  defined  areas 
of  relatively  normal  parenchyma  persist  and  present  a 
sharp  contrast  to  the  altered  tissue  which  is  dark  red, 
reddish  brown  or  even  reddish  black  in  color. 

Histological  peculiarities  of  the  lesion  have  explained 
its  relationship  to  hemorrhage  on  the  one  hand  and  to 
gangrene  on  the  other.  The  significance  of  extensive 
necrosis  of  the  parenchyma  which  is  an  essential  feature 
of  the  lesion  has  not  been  fully  recognized. 

In  five  cases  (II,  V,  YI  and  VII)  which  I  have 
described  the  symptoms  have  been  of  short  duration  and 
the  essential  features  of  the  lesion  are  well  illustrated. 
Wide-spread  necrosis  of  the  parenchyma  (Fig.  24)  is  asso- 
ciated with  hemorrhage  and  with  perhaps  trivial  accumu- 
lation of  inflammatory  products,  notably  fibrin  and 
polynuclear  leucocytes.  There  is  total  death  of  the 
tissue,  implicating  at  once  epithelial  cells,  interstitial 
connective  tissue,  and  walls  of  blood-vessels.  For  a  time 
the  architecture  of  the  tissue  is  preserved  and  the  out- 
lines of  the  acini  are  readily  discernible,  though  the 
nuclei  of  the  cells  are  wholly  lost.  Later  the  tissue 
undergoes  such  complete  alteration  that  the  structures 
composing  it  are  no  longer  recognizable.  Transition 
from  such  necrotic  material  to  living  tissue  is  abrupt, 
and  often  marked  by  a  narrow  zone  containing  fragments 


160  DISEASE  OF  THE  PANCREAS 

of  nuclei,  polynuclear  leucocytes,  red  blood-corpuscles, 
and  fibrin.  Acute  inflammation  is  not  constantly  present 
and  in  some  instances  (Case  VI)  there  is  little  or  no 
inflammatory  reaction.  Even  when  inflammatory  prod- 
ucts have  accumulated  in  one  part  of  the  tissue,  the  mar- 
gin of  necrotic  areas  elsewhere  may  exhibit  no  evidence 
of  inflammation.  Hyaline  thrombosis  of  capillaries 
occurs  within  the  relatively  intact  tissue  which  is  in 
contact  with  the  necrotic  zone.     (Cases  II  and  V.) 

By  experimental  means  it  is  possible  to  produce  a 
lesion  of  which  the  essential  features  are  those  observed 
in  human  cases,  but,  the  conditions  being  under  control, 
various  stages  in  the  process  can  be  more  readily  studied. 
In  two  experiments  in  which  death  has  followed  within 
twenty-four  hours  the  injection  of  5  c.c.  of  bile  into, 
the  pancreatic  duct,  foci  of  necrosis  contain  widely  dis- 
tended blood-vessels,  while  injury  to  their  walls  is  indi- 
cated by  the  escape  of  numerous  red  blood-corpuscles 
into  the  tissues  adjacent  to  them.  In  places  polynuclear 
leucocytes  are  present  in  moderate  number.  Prolifera- 
tion of  the  fixed  tissue  occurs  with  rapidity  and  the 
injured  parenchyma  is  invaded  and  replaced. 

In  both  human  and  experimental  lesions,  bile  coming 
into  contact  with  cells  causes  their  death,  and  necrosis 
of  the  parenchyma  is  associated  with  such  injury  to  the 
adjacent  vessel  walls  that  red  blood-corpuscles  escape 
in  great  abundance.  Inflammatory  and  reparatory 
changes  are  secondary  to  death  of  tissue  and  occur  at 
the  margin  of  the  necrotic  area.  Hemorrhage  may  be 
the  result  of  necrosis  before  inflammatory  changes  are 
well  marked.  Extensive  hemorrhage  is  doubtless  due  to 
necrosis  implicating  the  wall  of  some  vessel  of  consider- 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         l6l 

able  size.  Hemorrhage  on  the  contrary  may  be  an  insig- 
Dilicant  feature  of  an  otherwise  typical  instance  of 
pancreatic  necrosis.  In  Case  VI,  although  the  greater 
part  of  the  gland  had  undergone  necrosis,  only  a  few 
black  spots  gave  evidence  of  hemorrhage. 

Numerous  experiments  have  shown  that  a  variety  of 
substances,  including  bile,  injected  into  the  pancreas 
cause  wide-spread  necrosis,  which  finds  little  analogy 
in  other  organs.  The  pancreas,  a  gland  secreting  sub- 
stances which  effect  the  digestion  of  proteins  within  the 
intestine,  is  after  death  capable,  like  the  stomach,  of 
causing  partial  digestion  of  its  own  substance.  It  is  not 
improbable  that  enzjines  of  the  pancreatic  juice,  notably 
trypsin,  acting  upon  cells  injured  by  contact  with  the 
various  irritant  substances  which  can  produce  hemor- 
rhagic necrosis,  have  a  part  in  the  production  of  the 
wide-spread  disintegration  of  the  parenchyma  which 
results. 

Both  with  the  human  and  with  the  experimental  lesion 
of  hemorrhagic  necrosis  complete  recovery  may  occur. 
Necrotic  parenchyma  is  absorbed  and  replaced  by  fibrous 
tissue ;  the  presence  of  iron-containing  pigment  may  give 
evidence  of  old  hemorrhage.  Partial  recovery  is  illus- 
trated by  Cases  I  and  IV,  in  which  bands  of  newly  formed 
fibrous  tissue  separate  and  replace  lobules  of  pancreatic 
parenchyma.  In  such  cases  fluid  which  may  have 
accumulated  in  the  lesser  peritoneal  cavity  is  not  ab- 
sorbed after  the  pancreatic  lesion  has  healed.  The  cav- 
ity contains  opaque  fluid  and  necrotic  particles  and  the 
pancreas  is  covered  by  black  altered  blood ;  the  condition 
is  occasionally  though  incorrectly  described  as  peripan- 
11 


162  DISEASE  OF  THE  PANCREAS 

creatitis,  the  original  pancreatic  lesion  having  almost 
wholly  disappeared. 

Stage  of  Gangrene. — Though  the  older  literature  con- 
tains cases  in  which  the  pancreas  has  undergone  seques- 
tration, an  adequate  picture  of  the  condition  has  been 
first  drawn  by  Fitz,  who  has  shown  that  acute  pancrea- 
titis may  terminate  in  gangrene.     From  a  study  of  fif- 
teen cases  Fitz  found  that  the  appearance  of  the  pancreas 
varies  with  the  duration  of  the  disease.     The  gland,  he 
says,  is  at  first  swollen,  dark  red,  and  soft,  while  on 
section  the  tissue  is  red  or  mottled  red  and  gray,  or  may 
be  wholly  transformed  into  a  dark  slate-colored,  foul- 
smelling  mass.    At  the  end  of  about  ten  days  the  pan- 
creas is  often  dark  brown,  dry  and  firm,  and  covered  by 
changed  blood;  hemorrhagic  infiltration  may  extend  be- 
yond  its   limits.      Throughout   the   substance   areas   of 
hemorrhage  alternate  with  yellow  spots  of  softening. 
At  the  end  of  the  second  week  the  organ  may  form  a  soft, 
black,  friable  mass,  while  the  lesser  omental  cavity  con- 
tains a  large  quantity  of  chocolate-colored  fluid  contain- 
ing large,  bluish-black  clots.     The  gland  may  be  finally 
transformed  into  a  soft  mass  attached  by  a  few  shreds 
to  the  posterior  abdominal  wall  or,  indeed,  may  lie  free 
in  the  omental  cavity,  which  is  distended  with  bloody  or 
blackish,  often  ill-smelling,  fluid  containing  necrotic  par- 
ticles of  tissue.     A  conspicuous  feature  is  the  occurrence 
of  disseminated  fat  necrosis. 

Histological  examination  of  human  cases  and  study 
of  so-called  hemorrhagic  pancreatitis  produced  experi- 
mentally has  shown  that  extensive  necrosis  of  tissue  is 
associated  with  injury  to  the  blood-vessels  and  conse- 
quent hemorrhage.    Wide-spread  death  of  tissue  is  pri- 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         163 

mary,  and  subsequent  alterations  due  to  changes  occur- 
ring in  the  extravasated  blood  and  to  invasion  of  bacteria 
cause  such  discoloration  and  disintegration  of  the 
affected  tissue  that  it  is  recognized  by  the  naked  eye  to 
be  gangrenous.  Suppuration  with  or  without  perfora- 
tion of  the  gastro-intestinal  tract  is  a  secondary  change 
and  is  not  the  cause  of  the  gangrenous  condition.  No 
sharp  distinction,  therefore,  can  be  drawn  between  hemor- 
rhagic and  so-called  gangrenous  pancreatitis.  The  lesion 
begins  with  necrosis  of  tissue,  and  hemorrhage  takes 
place  into  the  necrotic  area ;  there  is  bacterial  invasion, 
and  should  sufficient  time  elapse  those  alterations  which 
give  to  the  organ  the  macroscopic  appearance  of  gan- 
grene ensue. 

Hemorrhagic  necrosis  of  the  pancreas  appears  to  be 
more  rapidly  fatal  in  men  than  in  women,  for  among 
forty-one  instances  in  which  the  lesion  has  been  described 
as  hemorrhagic  pancreatitis  Korte  has  found  only  four  in 
women,  whereas  among  forty  cases  which  have  reached 
the  stage  of  gangrene,  nineteen  have  been  in  women. 

Accumulation  of  Fluid  within  the  Lesser  Peritoneal 
Cavity. — With  necrosis  of  pancreatic  parenchyma  in  con- 
tact with  the  overlying  peritoneum  and  with  necrosis  of 
fat  below  the  lesser  peritoneal  membrane  there  is 
accumulation  of  fluid  within  the  bursa  omentalis.  Ad- 
hesions close  the  foramen  of  Winslow  and  separate  the 
lesser  from  the  general  peritoneal  cavity.  The  fluid 
which  accumulates  contains  products  of  pancreatic  secre- 
tion; necrosis  and  erosion  of  adjacent  tissues  is  doubtless 
due  to  action  of  fat-splitting  and  proteolytic  enzymes. 
At  first  the  contents  of  the  cavity  may  be  sterile  (Case 
IV),  but  later  bacteria  find  their  way  from  the  gangren- 


164  DISEASE  OF  THE  PANCREAS 

ous  pancreas  in  contact  with  the  duodenum  to  the  peri- 
toneal surface  of  the  gland.  In  Case  I,  in  which  death 
occurred  after  twenty-one  days,  Bacillus  coli,  Bacillus 
lactis  aerogenes,  and  Bacillus  proteus  vulgaris  were  ob- 
tained, and  in  Case  IV,  with  death  two  months  after 
onset  of  illness,  Bacillus  coli  and  Streptococcus  pyogenes 
were  found  at  autopsy. 

The  wall  of  the  abscess  cavity  is  formed  in  large  part 
by  soft  necrotic  fat  which  is  usually  blackish  or  gray. 
There  is  abundant  brown  or  gray  fluid  which  contains 
soft  greasy  necrotic  material.  Erosion  of  the  retroperi- 
toneal tissue  to  the  left  of  the  root  of  the  mesentery  not 
infrequently  occurs  and  in  some  instances  (Case  IV)  a 
sinus  penetrates  the  abdominal  wall  and  approaches  the 
surface  of  the  body  in  the  left  lumbar  region.  Erosion 
of  tissue  behind  the  pancreas  may  form  a  communication 
with  the  general  peritoneal  cavity,  and  in  Case  IV  an 
immense  sub-diaphragmatic  abscess  had  perforated  the 
diaphragm  and  caused  localized  empyema.  Erosion 
from  without  may  cause  perforation  of  stomach,  duode- 
num or  transverse  colon,  and  in  Case  III  all  of  these 
organs  have  been  perforated  by  an  abscess  about  a  gan- 
grenous pancreas.  Discharge  of  necrotic  pancreatic 
tissue  from  the  bowel  is  recorded  by  Chiari. 

SYMPTOMS. 

The  foregoing  study  has  shown  that  no  sharp  distinc- 
tion can  be  drawn  between  pancreatic  hemorrhage, 
hemorrhagic  pancreatitis,  and  gangrenous  pancreatitis. 
These  processes  are  essentially  wide-spread  necrosis  of 
the  parenchjTna,  associated  with  injury  to  the  walls  of 
blood-vessels,    and    hemorrhage;    so-called    gangrenous 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         165 

pancreatitis  is  a  late  stage  of  the  hemorrhagic  lesion: 
the  gland  primarily  undergoes  necrosis.  Whereas  other 
causes,  notably  traumatism,  may  produce  the  condition, 
the  most  frequent  etiological  factor  is  the  impaction  of  a 
gall-stone  in  the  diverticulum  of  Vater,  diverting  bile 
into  the  pancreatic  duct. 

Stage  of  Hemorrhage. — An  individual  usually  in 
fairly  good  health,  with  perhaps  a  history  of  gastric 
disturbance  or  of  gall-stone  colic,  is  suddenly  attacked 
with  pain  in  the  epigastric  region,  accompanied  by  vomit- 
ing and  followed  by  collapse. 

Pitz  describes  as  follows  the  symptoms  of  acute 
hemorrhagic  pancreatitis:  "It  begins  with  intense  pain, 
especially  in  the  upper  abdomen ;  soon  followed  by  vomit- 
ing, which  is  likely  to  be  more  or  less  obstinate,  and  not 
infrequently  by  slight  epigastric  swelling  and  tenderness, 
with  obstinate  constipation.  A  normal  or  subnormal 
temperature  may  be  present,  and  symptoms  of  collapse 
precede,  by  a  few  hours,  death,  which  is  most  likely  to 
occur  between  the  second  and  fourth  days. ' ' 

The  pain  of  onset  appears  suddenly  and  is  of  great 
intensity;  it  may  be  paroxysmal  or  continuous.  It  is 
occasionally  localized  above  the  umbilicus  and  to  the  left 
of  the  median  line  along  the  course  of  the  pancreas,  but 
may  be  most  intense  in  the  hypochondriac  regions  or 
even  below  the  umbilicus.  Nausea  and  vomiting  rapidly 
follow  the  appearance  of  pain  and  may  recur  with  great 
frequency. 

Symptoms  of  shock  usually  accompany  the  disease 
and  within  a  few  hours  may  cause  death.  Profound 
weakness  is  accompanied  by  depression  of  the  circula- 
tory system;  the  pulse  is  rapid,  and  circulation  may  be 


166  DISEASE  OF  THE  PANCREAS 

so  feeble  that  cyanosis  results.  The  profound  collapse 
and  rapidly  fatal  termination  of  many  cases  of  hemor- 
rhagic necrosis  suggest  the  presence  of  an  acute  intoxica- 
tion. A  similar  condition  follows  the  lesion  produced 
experimentally  in  dogs,  and  death  within  twenty-four 
hours  may  be  caused  by  the  injection  of  5  c.c.  of  bile  into 
the  pancreatic  duct.  The  pancreatic  enzymes,  perhaps 
increased  in  activity  by  presence  of  bile,  act  doubtless 
upon  the  substance  of  the  gland  and  produce,  both  in  the 
human  and  experimental  lesion  products  which,  when 
absorbed,  exert  a  profoundly  poisonous  action.  Such  an 
explanation  of  the  fatal  result  appears  more  probable 
than  that  which  seeks  to  refer  the  symptoms  of  collapse 
or  shock  to  an  obscure  lesion  of  the  sympathetic  ganglia 
near  the  pancreas. 

To  prove  that  death  is  due  to  a  toxic  substance  derived 
from  injured  pancreatic  tissue,  Doberauer  ^^  has  trans- 
ferred pancreatic  tissue  rendered  necrotic  by  obstruction 
of  its  blood  supply  into  the  peritoneal  cavity  of  a  normal 
animal.  Death  has  occurred  with  symptoms  which  are 
similar  to  those  of  hemorrhagic  necrosis  of  the  pancreas 
produced  by  other  experimental  methods ;  the  possibility 
of  bacterial  action  has  been  excluded.  Gulecke^^  has 
claimed  that  pancreatic  tissue  of  a  normal  dog  introduced 
into  the  peritoneum  of  a  second  animal  causes  death 
within  twenty-four  hours,  whereas  pancreatic  tissue 
allowed  to  undergo  autolysis  is  more  rapidly  fatal;  he 
attributes  symptoms  of  pancreatic  necrosis  to  absorption 
of  pancreatic  secretion  and  to  products  formed  by  disinte  - 


Doberauer:  Beit.  z.  klin.  Cliir.,  1906,  xlviii,  456. 
'  Loc.  eit.,  p.  127. 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         167 

gration  of  pancreatic  tissue.  Egdalil  ^"  has  shown  that 
pancreatio  extracts  allowed  to  undergo  autolysis  are 
capable  of  depressing  blood-pressure;  their  toxic  effect 
is  greatest  when  digestion  has  gone  so  far  that  protein 
constituents  of  the  extract  have  been  destroyed. 

Since  hemorrhagic  necrosis  may  be  caused  by  the 
lodgement  of  a  gall-stone  in  the  diverticulum  of  Vater, 
patients  suffering  with  this  disease  not  infrequently  give 
a  history  of  preceding  gall-stone  colic.  In  Case  I  the 
patient  underwent  an  attack  of  jaundice  six  months  be- 
fore his  fatal  illness.  In  other  instances  there  is  a  his- 
tory of  repeated  paroxysms  of  severe  abdominal  pain, 
doubtless  due  to  the  passage  of  calculi  which  have  failed 
to  lodge  at  the  orifice  of  the  bile  duct.  Preceding  attacks 
of  so-called  gastric  or  gastroduodenal  dyspepsia,  noted 
by  Fitz,  in  some  cases  at  least  admit  of  a  similar  explana- 
tion. Moreover,  symptoms  of  the  pancreatic  disease  may 
be  mistaken  for  those  of  biliary  colic;  jaundice  has  been 
present  in  ten  per  cent,  of  the  cases  collected  by  Gessner. 
Intensity  of  the  pain,  its  diffuse  epigastric  character, 
with  occasional  localization  on  the  left  side,  and  the  pro- 
found collapse  usually  present,  according  to  Thayer,  give 
sufficient  evidence  that  the  pancreas  is  implicated. 

Symptoms  suggesting  intestinal  obstruction  have  been 
present  in  a  large  proportion  of  cases  and  not  infre- 
quently operation  has  been  undertaken  with  the  purpose 
of  relieving  such  obstruction.  Constipation  which  is 
present  in  about  half  of  the  cases  of  pancreatic  necrosis 
is  not  infrequently  relieved,  according  to  Gessner,^^  either 

■^  Egdahl :  Jour,  of  Exper.  Med.,  1907,  ix,  385. 
•"  Gessner :  Deutsche  Zeit.  f .  Chir.,  1899,  xliv,  65. 


168  DISEASE  OF  THE  PANCREAS 

spontaneous!}"  or  by  means  of  enemata  on  the  fourth  day 
of  the  disease.  Gessner  has  found  in  the  literature  of  the 
subject  six  cases  in  which  the  enlarged  head  of  the  pan- 
creas appeared  to  compress  the  duodenum;  but  in  most 
instances  symptoms  suggesting  intestinal  obstruction 
can  not  be  exjDlained  by  mechanical  occlusion  of  the  in- 
testine. Some  writers  have  thought  that  irritation  of  the 
solar  plexus  and  splanchnic  nerve  may  inhibit  peristalsis. 

With  sjTuptoms  of  intestinal  obstruction  diagnosis  of 
pancreatic  necrosis  may  be  suggested  by  the  localization 
of  pain  and  distention  in  the  epigastric  region.  The 
stercoraceous  vomiting  and  visible  peristalsis  of  intes- 
tinal obstruction  are  not  present. 

Stage  of  Gangrene. — The  violent  symptoms  of  onset 
may  diminish  in  intensity;  Gessner  regards  the  fourth 
day  as  critical.  When  death  does  not  occur  opportunity 
is  afforded  for  invasion  of  bacteria  and  for  other  changes 
associated  with  so-called  gangrenous  pancreatitis;  this 
transition  occurs  toward  the  end  of  the  second  week  of 
the  disease. 

In  many  instances  the  symptoms  of  onset  are  much 
less  severe  than  those  which  have  been  described,  and, 
perhaps  associated  with  an  attack  of  gall-stone  colic,  may 
be  so  slight  as  to  be  unrecognizable.  The  patient  sur- 
vives and  the  disease  pursues  a  more  or  less  chronic 
course.  The  symptoms  are  essentially  those  previously 
mentioned,  but  they  occur  with  less  intensity.  Pain  is 
localized  in  the  epigastrium,  and  vomiting  may  recur  at 
intervals.  Symptoms  indicative  of  suppuration  finally 
give  evidence  that  the  necrotic  tissue  of  the  pancreas  has 
become  infected ;  an  irregular  temperature,  perhaps  with 
chills,  may  suggest  the  presence  of  abscess,  but  occasion- 
allv  fever  is  absent.     An  ill-defined  tumor  felt  above  the 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         169 

umbilicus  gives  more  positive  proof  that  fluid  has  accu- 
mulated about  the  pancreas  in  the  lesser  peritoneal 
cavity.  The  appearance  of  such  a  mass  in  the  epigastric 
region  is  due,  not  to  the  enlarged  pancreas,  which  is 
rarely  if  ever  palpable,  but  to  the  presence  of  hemor- 
rhagic or  purulent  fluid  about  the  organ. 

The  tumor  mass  is  usually  situated  in  the  epigastric 
region  and  extends  toward  the  spleen;  it  varies  much  in 
size  and  its  outline  is  usually  definable  with  difficulty. 
Such  tumors  as  large  as  a  child's  head  have  been  de- 
scribed. In  three  cases  of  Korte  a  mass  first  found  in 
the  left  hypochondrium  and  flank  subsequently  became 
palpable  between  stomach  and  colon.  Inflation  of  the 
stomach  and  in  some  instances  of  the  colon  may  aid  in 
localizing  the  mass  which,  occupying  the  bursa  omentalis, 
is  situated  between  these  two  organs.  The  stomach  sepa- 
rates the  tumor  from  the  liver  and  when  inflated  tends 
to  cover  it.  Not  infrequently  there  is  a  tendency  for 
the  abscess,  situated  within  the  lesser  peritoneal  cavity, 
to  erode  the  tissue  over  the  left  kidney  (Cases  I  and  IV). 
A  sinus  from  the  cavity  may  make  its  way  into  the  lumbar 
region  and  cause  swelling  below  the  left  costal  margin 
as  far  as  the  crest  of  the  ilium. 

Both  in  the  hemorrhagic  and  in  the  gangrenous  stage 
of  the  disease,  those  disturbances  of  digestion  which  have 
been  noted  in  describing  the  general  symptomatology  of 
pancreatic  disease  ma}^  occur,  but  rarely  is  there  such 
complete  destruction  of  the  pancreas  that  its  functional 
activity  is  wholly  destroyed.  Fatty  stools  have  been 
found  in  only  one  instance  (Chantemesse  and  Griffon '^^). 
In  Case  I  (see  also  case  of  Dr.  Kelly,  p.  174),  the  patient 

"'Chantemesse  and  Grifeon:  Bull.    Soe.  anat.,  Paris,  1895,  587. 


170  DISEASE  OF  THE  PANCREAS 

passed  clay-colored  stools  due  perhaps  to  occlusion  of 
both  biliary  and  pancreatic  ducts.  In  two  cases  of  Chiari 
necrotic  pancreatic  tissue  identified  by  careful  examina- 
tion was  expelled  from  the  rectum  and  recovery  followed. 
In  only  two  of  the  forty-one  cases  of  so-called  hemor- 
rhagic pancreatitis,  and  in  but  three  of  forty  cases  of 
gangrenous  inflammation  collected  by  Korte,  was  sugar 
jDresent  in  the  urine.  Transient  glycosuria  has  occasion- 
ally been  observed  shortly  after  onset  of  symptoms. 

In  a  ease  described  bj'  Benda  and  Stadelmann  "^  symptoms  were 
those  of  diabetic  coma.  Almost  immediately  after  onset  of  violent 
abdominal  pain  the  patient  became  comatose;  sugar  was  found  in  the 
urine.  The  pancreas,  save  a  part  of  the  head,  was  transformed  into  a 
soft  bloody  mass. 

Diabetes  consequent  upon  hemorrhagic  necrosis  of  the  pancreas  has 
been  described  by  Franke.'"  A  man,  aged  forty-two  years,  who  had  pre- 
viously enjoyed  good  health,  was  attacked  twelve  days  before  his 
death  with  severe  abdominal  pain,  accompanied  by  vomiting.  The 
pain,  which  was  localized  in  the  region  of  the  umbilicus,  continued, 
and  the  patient  complained  much  of  thirst.  When  seen,  eight  days 
after  the  onset  of  symptoms,  sugar  was  found  in  the  urine,  and  to  the 
amount  of  3.5  per  cent,  was  present  until  death.  The  fat  of  the 
parietal  peritoneum,  omentum,  mesentei-y,  and  mediastinum  contained 
numerous  foci  of  necrosis.  The  pancreas  was  represented  by  a  large 
blackish-red  mass,  which  consisted  in  great  part  of  altered  blood,  but 
in  a  few  places  still  preserved  a  lobular  structure.  The  gall-bladder 
was  distended  and  contained  a  calculus  about  the  size  of  a  plum. 

AVith  hemorrhagic  necrosis  leucocytosis  may  be  pres- 
ent during  the  first  few  days  after  onset  of  symptoms ;  in 


•^  Benda    and     Stadelmann:  Deutsche     med.    Woeh.,     LS9G,     xxii, 
Vereins-Beilage,  138. 

'°  Franke  :  Inaug.  Diss.,  Berlin,  1902. 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         171 

a  case  described  by  Hunt^^  leucocytes  numbered  37,000 
per  cubic  millimetre  on  the  first  day  of  illness.  Never- 
theless, leucocytosis  is  not  constant.  (See  Case  VI,  in 
which  leucocytes  numbered  9900  per  cubic  millimetre  on 
the  fourth  day  of  the  disease.)  With  so-called  gangren- 
ous pancreatitis  leucocytes  usually  vary  between  15,000 
and  40,000  per  cubic  millimetre.  Case  IV  shows  that 
their  number  may  diminish  with  progress  of  the  disease, 
becoming  subnormal  before  death. 

In  some  reported  cases  recurrent  pancreatitis  has 
been  described,  but  attacks  of  severe  pain  and  vomiting 
preceding  the  fatal  illness  are  doubtless  often  referable 
to  cholelithiasis.  Nevertheless,  it  cannot  be  denied  that 
pancreatic  necrosis  may  recur;  for  should  the  patient 
survive  a  primary  attack,  the  structure  of  the  diverticu- 
lum of  Vater  being  favorable,  a  second  attack  might 
follow  the  expulsion  of  another  stone  of  appropriate  size. 

TREATMENT. 

What  has  been  said  concerning  the  etiology  and 
pathology  of  acute  inflammation  of  the  pancreas  demon- 
strates the  futility  of  medical  treatment  directed  to  palli- 
ation of  the  lesion.  At  the  onset  of  symptoms  the  atten- 
tion of  the  physician  will  be  directed  to  the  profound 
collapse,  and  efforts  will  be  made  to  strengthen  the  en- 
feebled circulation.  The  intense  abdominal  pain  is  often 
uncontrollable  by  the  use  of  morphia.  For  the  continued 
vomiting  Korte  recommends  that  the  stomach  be  washed 
out,  food  by  mouth  discontinued,  and  nutrient  and  stimu- 
lating enemata  employed. 

"  Hunt :  Boston  Med,  and  Surg.  Jour.,  1905,  elii,  13. 


172  DISEASE  OF  THE  PANCREAS 

Only  by  surgical  means  can  tlie  seat  of  the  disease  be 
reached.  AVlien  it  is  possible  to  make  a  diagnosis  of 
hemorrhagic  necrosis  of  the  pancreas  the  advisability  of 
operation  during  the  first  stage  of  the  disease  must  be 
considered.  Both  liahn'^  and  Woolsey,'^^  who  have  re- 
corded cases  in  which  operation  has  been  followed  by 
recovery,  point  out  the  danger  of  increasing  the  shock 
present  in  such  cases  by  prolonged  operations  and  by 
manipulation  of  the  intestines.  Statistics  of  G-essner 
give  evidence  that  operation  during  the  first  two  weeks 
is  more  frequently  fatal  (only  one  of  twenty-two  patients 
recovered)  than  operation  undertaken  during  the  stage 
of  gangrene  (six  recoveries  after  twenty  operations). 
The  larger  statistics  of  Mikulicz-Eadecki  "'^  published 
in  1903  recorded  more  favorable  results;  among  forty- 
six  operations  performed  in  the  early  stage  of  the  disease 
there  were  nine  recoveries,  and  among  thirty-five  opera- 
tions in  the  subacute  stage,  eighteen  recoveries.  Since 
the  mortality  of  untreated  cases  is  unknown  these  figures 
have  little  value.  Mikulicz-Eadecki  recommends  early 
operation  with  evacuation  of  hemorrhagic  exudate  which 
is  often  present  in  the  lesser  peritoneal  cavity,  and  free 
drainage  by  gauze. 

Hemorrhage  is  rarely  profuse  and  bears  little  relation 
to  the  severity  of  the  condition.  In  some  cases  symptoms 
are  so  indefinite  that  hemorrhagic  necrosis  of  the  pan- 
creas is  not  suspected,  whereas  in  other  instances,  though 
such  a  lesion  suggests  itself,  the  evidence  is  insufficient 

"  Hahn :  Deutsche  Zeit.  f .  Chir.,  1900,  Iviii,  1. 
"Woolsey:    Ann.  of  Surg.,  1903,  xxxviii,  603. 
"  Von  Mikulicz-Radeeki :  Trans,  of  the  Cong-,  of  Amer.  Phys.  and 
Surg.,  1903,  vi,  55. 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         173 

to  exclude  the  presence  of  other  conditions.  Experience 
has  shown  that  the  disease  is  often  first  recognized  by 
the  presence  of  fat  necrosis  noted  at  operation  under- 
taken for  the  relief  of  a  supposed  intestinal  obstruction 
or  perhaps  performed  for  the  purpose  of  exploration 
demanded  by  continued  symptoms  of  grave  abdominal 
disorder.  Should  the  individual  survive  the  early  symp- 
toms of  shock,  infection  of  the  gangrenous  tissue  and 
abscess  formation  limited  to  the  lesser  peritoneal  cavity 
soon  demand  exploration  and  drainage.  Septic  fever, 
and  the  presence  of  a  palpable  mass  in  the  epigastrium, 
indicate  the  necessity  of  operative  interference. 

When  disseminated  fat  necrosis  indicates  the  presence 
of  a  pancreatic  lesion,  exploration  of  the  lesser  peritoneal 
cavity  through  the  gastrocolic  omentum  may  disclose  the 
presence  of  a  pancreatic  or  peripancreatic  abscess  and 
permit  its  evacuation.  Thick  abdominal  walls  and  omen- 
tal fat  in  large  quantity,  together  with  an  accumulation 
of  necrotic  tissue  and  partially  clotted  blood  within  the 
lesser  peritoneal  cavity,  at  times  make  access  to  the  pan- 
creas itself  difficult  or  impossible,  at  least  undesirable. 

Incision  is  usually  made  in  the  median  line  or  over 
the  most  prominent  part  of  the  tumor  mass  and  the 
abscess-like  cavity  is  entered  through  the  gastrocolic  liga- 
ment. The  operation  is  facilitated  by  adhesions  binding 
this  part  of  the  omentum  to  the  abdominal  wall,  and 
Korte  recommends  that  the  gastrocolic  ligament  be 
stitched  to  the  abdominal  wall  about  the  incision  when 
they  are  absent;  the  general  peritoneal  cavity  may  be 
protected  by  gauze.  Fluid  together  with  particles  of 
necrotic  tissue  contained  in  the  peritoneal  cavity  are 
evacuated.     When  the  cavity  extends  far  to  the  left  it 


174  DISEASE  OF  THE  PANCREAS 

Biay  be  possible  to  obtain  more  effective  drainage  by  a 
second  incision  to  the  left  of  the  first.  When  erosion  has 
occurred  through  the  retroperitoneal  tissue  into  the  left 
flank,  the  cavity  may  be  reached  through  a  horizontal 
or  oblique  incision  similar  to  that  employed  for  extirpa- 
tion of  the  left  kidney  (Korte).  For  efficient  drainage 
incisions  both  in  the  ejjigastric  and  in  the  left  lumbar 
regions  may  be  necessary. 

During  whatever  stage  of  the  disease  operation  is 
performed,  the  condition  of  the  bile  passages  is  impor- 
tant and  may  offer  an  indication  for  interference.  The 
common  bile  duct  should  be  examined  so  far  as  it  is 
possible,  and,  bearing  in  mind  the  mechanism  by  which  a 
small  calculus  may  produce  the  lesion,  the  operator 
should,  if  feasible,  exclude  the  possibility  that  a  stone  is 
still  lodged  in  the  diverticulum  of  Vater.  Should  such 
impaction  be  found,  removal  of  the  calculus  is  essen- 
tial in  order  to  prevent  further  destruction  of  the  pan- 
creas. In  a  considerable  number  of  cases  the  gall-blad- 
der will  be  found  filled  with  gall-stones,  even  though 
the  bile  ducts  are  free.  These  stones  may  be  of  such  size 
that  any  one  of  them  lodged  at  the  orifice  of  the  common 
duct  might  divert  bile  into  the  pancreatic  duct. 

In  a  patient  with  acute  pancreatic  disease  and  fat 
necrosis,  operated  upon  by  Dr.  Howard  A.  Kelly,  recov- 
ery followed  the  removal  of  a  large  number  of  small 
gall-stones  from  the  gall-bladder. 

Mrs.  W.,  aged  forty-one  years,  was  admitted  to  the  care  of  Dr. 
Kelly,  May  17,  1002.  For  several  years  preceding,  she  had  suffered 
with  attacks  of  pain  in  the  epigastrium.  Her  present  illness  began 
with  severe  pain  in  the  left  side  and  back,  lasting  about  three  days,  and 


Fig.  25. — Calculi  which  were  removed  from  the  gall-bladder  by  Dr.  Kelly ;  compare 

with  Fig.  12. 


HEMORRHAGIC  NECROSIS  OF  PANCREAS         175 

subseqviently  reeumng  in  paroxysms,  necessitating  the  i;se  of  morphia. 
There  was  slight  nausea,  but  no  vomiting.  The  stools  were  clay-colored 
and  of  vei-y  foul  odor;  the  temperature  varied  from  98°  to  100°  F. 
An  operation  was  undertaken  on  the  tenth  day  of  illness.  The  omentum 
was  found  to  contain  opaque,  white  foci  of  fat  necrosis.  An  oblong 
mass  about  9  cm.  in  length  and  6  cm.  broad  lying  behind  the  greater 
curvature  of  the  stomach  occupied  the  position  of  the  pancreas. 
Further  examination  was  not  possible  on^  account,  of  the  great  quantity 
of  fat.  The  gall-bladder  was  found  partially  collapsed  about  a  large 
number  of  small  gall-stones.  An  incision  was  made  throughi  the  skin 
and  abdominal  wall  opposite  the  gall-bladder;  the  organ  was  stitched 
to  the  edges  of  the  wound  and  opened.  About  fifty  small  calculi  of 
almost  unifoim  size  were  removed  (see  Fig.  25).  The  wound  opposite 
the  gall-bladder  healed  slowly,  and  the  patient  made  an  uneventful 
recovery. 

In  the  preceding  case  necrosis  of  the  pancreas  and 
consequent  fat  necrosis  were  doubtless  caused  by  the 
passage  of  a  small  calculus  similar  to  calculi  so  numerous 
in  the  gall-bladder.  These  stones  differed  but  little  from 
those  which  filled  the  gall-bladder  in  Cases  I,  III  and  IV, 
and  were  of  the  same  uniform  size.  Their  removal 
offered  the  best  assurance  of  immunity  from  subsequent 
attacks.  Similar  instances  of  recovery  following  re- 
moval of  calculi  from  the  gall-bladder  of  individuals 
suffering  with  pancreatic  necrosis  are  described  by 
Mayo,^^  Lilienthal,''^^  and  Robson  and  CammidgeJ^ 

"Mayo:    Jour,  of  the  American  Med.  Assoc,  1902,  xxxviii,  107. 

"  Lilienthal :  Ann.  of  Surg.,  1906,  sliii,  143. 

"  Robson  and  Cammidge :    The  Pancreas,  p.  397, 


CHAPTER  VII. 

FAT    NECROSIS. 

Repeated  reference  has  been  made  to  the  occurrence 
of  necrosis  of  fat  in  association  with  hemorrhagic  ne- 
crosis and  other  lesions  of  the  pancreas.  Disseminated 
focal  fat  necrosis  has  been  the  subject  of  much  anatomical 
and  experimental  research  since  Balser  directed  atten- 
tion to  it  in  1882,  and  the  relationship  of  this  peculiar 
lesion  to  alterations  of  the  pancreas  is  now  well  estab- 
lished. 

Balser  ^  observed  in  fat  immediately  about  the  pan- 
creas small,  opaque,  white  areas,  which  were  shown  by 
microscopic  examination  to  be  composed  in  great  part 
of  necrotic  fat-cells.  This  lesion  was  present  in  five  of 
twenty-five  bodies  which  he  examined.  In  two  cases  a 
similar  process  not  only  implicated  the  fat  about  the 
pancreas,  but  was  present  in  scattered  foci  at  a  consider- 
able distance  from  the  organ,  and  was,  he  believed,  the 
cause  of  death. 

When  widely  scattered  the  condition  has  been  desig- 
nated disseminated  or  multiple  fat  necrosis.  The  more 
minute  foci,  limited  to  fat  within  or  upon  the  organ, 
when  carefully  sought  for,  are  often  found  at  autopsy, 
but  their  frequency  is  somewhat  less  than  Balser 
supposed. 

Recognition  of  disseminated  fat  necrosis,  difficult  only 
on  account  of  the  relative  infrequency  with  which  it  is 

'  Balser :  Ueber  Fettnekrose,  Virchow's  Arch.,  1882,  xc,  520. 
176 


FAT  NECROSIS  177 

encountered,  is  of  considerable  importance  to  the  sur- 
geon, since  it  indicates  the  existence  of  some  grave  alter- 
ation of  the  pancreas.  On  opening  the  abdomen  the 
omentum,  and  possibly  other  fat,  is  found  studded  with 
round  or  oval  areas,  several  millimetres  in  diameter  and 
very  conspicuous  on  account  of  their  opaque  white  or 
yellow  color,  which  is  in  sharp  contrast  with  the  translu- 
cent golden  yellow  of  the  normal  fat.  A  narrow  hemor- 
rhagic zone  frequently  surrounds  such  areas. 

This  lesion,  most  extensive  in  the  neighborhood  of  the 
pancreas,  is  usually  limited  to  the  fat  of  the  abdominal 
cavitjT".  Areas  of  necrosis  may  be  confluent  near  the 
gland  and  thickly  scattered  elsewhere  in  the  fat  abutting 
upon  the  peritoneal  cavity.  In  two  cases  Hansemann- 
observed  foci  of  fat  necrosis  in  the  subcutaneous  tissue ; 
they  corresponded  in  location  to  reddish  areas  visible 
during  life  upon  the  overlying  skin.  Chiari  ^  has  re- 
corded a  very  remarkable  case:  areas  of  fat  necrosis, 
often  as  large  as  a  pea,  were  present  in  the  fatty  tissue 
about  the  bursa  omentalis  within  which  lay  the  necrotic 
pancreas,  in  the  mesentery,  in  the  subperitoneal  fat  of  the 
abdominal  wall,  in  the  subpericardial  and  subpleural  fat, 
and  in  the  subcutaneous  tissue,  Balser  has  also  seen 
the  pericardial  fat  implicated  in  the  process. 

Spontaneous  fat  necrosis  has  been  found  in  domestic 
animals  by  several  observers, — Balser,  Williams,^  Olt,^ 
and  others.     In  pigs  wide-spread  dissemination  of  the 

^  Hansemann :  Berlineri  med.  Gesellsch.,  Sitzung  vom  4  December, 
1889 ;  Berliner  klin.  Woeh.,  1889,  xxvi,  1115. 

'  Chiari :  Prager  med.  Woeb.,  1883,  viii,  285,  297. 

■*  Williams :  Report   of  tbe  Path.   Lab.   of  tbe  Univ.   of  Buffalo, 
1900,  No.  1. 

''  Olt :  Deutsche  Thierarztl.  Woch.,  1898,  vi,  117. 
12 


178  DISEASE  OF  THE  PANCREAS 

lesion  has  been  found  by  Olt,  who  records  its  presence 
in  the  subperitoneal  fat,  in  the  intermuscular  septa,  and 
in  the  subcutaneous  tissue  of  the  abdominal  and  thoracic 
walls. 

Chiari  found  fat  necrosis  in  five  of  six  instances  of 
pancreatic  disease.  Fitz  offered  the  suggestion  that  fat 
necrosis  was  consequent  upon  a  lesion  of  the  pancreas, 
and  supported  this  conclusion  by  numerous  instances  in 
which  the  two  conditions  had  been  associated.  The  lesion 
which  usually  accompanies  fat  necrosis  is  hemorrhagic 
necrosis  of  the  pancreas  and  not  infrequently  the  organ 
is  found  to  be  gangrenous  in  appearance.  Occasionally 
the  gland  lies  in  the  cavity  of  the  bursa  omentalis  dis- 
sected almost  free  from  the  surrounding  tissue;  such 
sequestration,  Langerhans  has  thought,  may  be  the  re- 
sult of  extensive  necrosis  of  the  fat  surrounding  it. 
More  rarely  other  pathological  conditions  are  present; 
chronic  suppurative  pancreatitis  is  rarely  accompanied 
by  fat  necrosis,  and  in  a  few  instances  chronic  interstitial 
inflammation  has  coexisted  with  it. 

The  occurrence  of  fat  necrosis  in  association  with 
pancreatic  disease  has  been  frequently  noted  in  individ- 
uals with  abundant  fatty  tissue.  In  the  statistics  of 
Truhart  corpulence  has  been  present  in  50  per  cent, 
of  cases  with  fat  necrosis;  in  90  of  267  cases  he  desig- 
nates the  condition  ohesitas  universalis.  In  43  cases 
infiltration  of  the  pancreas  with  fat  (lipomatosis)  was 
noted. 

The  microchemical  and  histological  studies  of  R.  Lan- 
gerhans^  have   explained   the  essential  nature  of  the 

°  Lang^erhans,  R. :     Ueber  multiple  Fettgewebsnekrose,  Virehow's 
Arch.,  1890,  exxii,  252. 


<^,N. 


Fig.  26. — Focus  of  fat  necrosis.  Fat  cells  have  lost  their  nuclei  but  retain  their  outline  ; 
calcium  deposited  in  some  of  the  necrotic  cells  causes  their  contents  to  stain  deeply  w-ith 
hrematoxylin.  Nuclear  fragments  have  accumulated  at  the  periphery  of  the  necrotic  focus 
(hcematoxylin  and  eosin). 


FAT  NECROSIS  179 

process.  He  has  shown  that  the  changes  demonstrable 
within  the  fat-cells  are  associated  with  the  splitting  of 
the  fat  molecule  into  its  fatty  acid  and  the  soluble  con- 
stituent glycerin.  Fatty  acids  are  deposited  as  needle- 
like crystals  within  the  cell  which  has  lost  its  nucleus  and 
is  evidently  necrotic,  while  the  soluble  glycerin  is  ab- 
sorbed. Very  soon  the  fatty  acids  unite  with  calcium  to 
form  calcium  salts,  and  within  the  cellular  outline  which 
is  still  preserved  are  irregular,  often  globular  masses, 
in  which  the  presence  of  lime  salts  ma}^  be  demonstrated 
by  microchemical  reactions. 

Benda  '^  has  shown  that  acetate  of  copper  combines 
with  fatty  acid  present  in  necrotic  fat  and  produces  a 
bluish-green  compound;  calcium  salts  are  less  intensely 
stained,  whereas  neutral  fats  of  the  normal  fat-cells  are 
unchanged.  By  this  method  it  is  possible  to  identify 
single  necrotic  cells  or  groups  of  such  cells  so  small  that 
they  are  not  recognizable  and  fat  necrosis  may  be  demon- 
strable in  subjects  in  whom  none  has  been  found  at 
autopsy. 

Fragments  of  nuclei  which  have  been  destroyed  may 
be  abundant  at  the  edge  of  the  focus  of  necrosis  (Fig.  26). 
A  few  polynuclear  leucocytes  find  their  way  to  the 
periphery  of  the  necrotic  fatty  tissue,  but  when  numer- 
ous, their  presence  is  the  result  of  secondary  infection 
of  the  dead  tissue.  Proliferation  of  fixed  tissue  cells 
occurs  at  the  periphery  of  the  necrotic  area  and  is  most 
conspicuous  in  the  neighborhood  of  strands  of  connective 
tissue,  but  often  the  zone  of  reaction  is  not  complete, 
and  necrotic  cells  are  in  contact  with  those  which  are 


Benda :  Virchow's  Arch.,  1900,  clxi,  194. 


180  DISEASE  OF  THE  PANCREAS 

still  unchanged.  In  this  peripheral  zone  of  cellular  pro- 
liferation, in  addition  to  cells  of  lymphoid  type,  are  much 
larger  round  or  oval  cells  with  vesicular  nuclei  and 
abundant  cytoplasm  studded  with  minute  fat-globules — 
fat-cells  in  process  of  multiplication.  Similar  cells  are 
occasionally  multinucleated  and  of  such  size  that  they 
may  be  called  giant  cells. 

A  case  described  by  Korte  shows  that  foci  of  fat 
necrosis  may  disappear  completely.  At  operation  upon 
a  patient  with  acute  cholecystitis  typical  foci  of  necrosis 
were  found,  but  one  year  later  when  laparotomy  was  per- 
formed for  the  removal  of  gall-stones  there  was  no  evi- 
dence of  fat  necrosis.  Wells  ^  observed  complete  absence 
of  fat  necrosis  at  the  end  of  eleven  days  after  injection 
of  pancreatin  into  the  peritoneal  cavity  of  a  dog,  although 
necrosis  of  fat  had  been  found  when  the  abdomen  was 
opened  on  the  fourth  day  after  injection. 

Etiology. — Attempts  have  been  made  to  refer  the 
occurrence  of  fat  necrosis  to  the  action  of  micro-organ- 
isms, and  in  many  cases  bacteria  have  been  isolated  from 
the  lesion.  The  explanation  of  their  presence  is  doubt- 
less that  proposed  by  Welch,^  who  identified  Bacil- 
lus coli  in  association  with  so-called  hemorrhagic  pan- 
creatitis with  fat  necrosis.  Diphtheritic  and  ulcerative 
colitis  was  present,  and  the  colon  bacillus  was  found  not 
only  in  foci  of  fat  necrosis,  but  in  the  mesenteric  glands, 
the  liver,  the  bile,  the  lungs,  the  spleen,  and  the  kidneys. 
The  lesion  of  the  colon  had  apparently  facilitated  the 
invasion  of  Bacillus  coli,  and  its  presence  in  foci  of  fat 

"Wells:    Jour,  of  Med.  Res.,  1903,  ix,  70. 
"Welch:  Med.  News,  ISOl,  lix,  ()69, 


FAT  NECROSIS  181 

necrosis  was  thought  to  be  a  secondary  event  having  no 
relation  to  their  production.  This  opinion  has  been  held 
by  Hlava,  Fitz,  Leonhard,  and  others.  From  the  litera- 
ture of  the  subject  Truhart  ^^  collected  80  records  of 
careful  bacteriological  examination;  no  bacteria  were 
found  in  43  instances,  whereas  in  37,  bacteria  were  ob- 
tained from  the  pancreas,  from  the  peritoneal  fluid  or 
from  foci  of  necrosis.  Various  micrococci  were  found 
10  times,  bacilli,  usually  Bacillus  coli,  22  times,  and  un- 
identified micro-organisms  in  other  instances.  The  dis- 
cordant results  of  bacteriological  examinations  give  little 
support  to  the  opinion  that  the  lesion  is  caused  by  micro- 
organisms and  experimental  studies  oppose  it. 

The  proximity  of  foci  of  fat  necrosis  to  the  pancreas 
and  their  association  with  various  pancreatic  lesions 
have  suggested  the  possibility  that  products  of  this  organ 
are  active  in  their  causation.  To  test  this  hypothesis, 
Langerhans  injected  into  the  fat-tissue  of  rabbits  and 
dogs  an  infusion  prepared  with  antiseptic  precautions 
from  the  pancreas  of  rabbits,  and  in  one  of  thirteen 
experiments  succeeded  in  producing  in  the  perirenal  fat 
of  a  dog  a  small  opaque  focus  which  had  the  histological 
character  of  fat  necrosis,  but  was  accompanied  by  an 
acute  inflammatory  reaction.  He  reached  the  conclusion 
that  pancreatic  juice  acting  on  living  fat-tissue  might 
cause  necrosis. 

The  experiments  of  Hildebrand  ^^  and  Dettmer  ^^  are 
interesting  and  important.     By  placing  a  ligature  about 

'"  Truhart :  Multiple  abdominale  Fettgewebsnekrose,  Weisbaden, 
1902. 

"  Hildebrand :  Cent,  f .  Chir.,  1895,  xxii,  297. 
"  Dettmer :  Inaug.  Diss.,  Gottingen,  1895. 


182  DISEASE  OF  THE  PANCREAS 

the  pancreas  tliey  obtained  necroses  in  the  fat  near 
that  part  of  the  gland  distal  to  the  ligature.  In  other 
experiments  they  tied  the  veins  of  the  ligatured  part  to 
prevent,  as  Hildebrand  suggests,  the  possible  absorption 
of  the  obstructed  secretion.  The  gland-tissue  became 
congested  and  infiltrated  with  blood,  and  in  its  neighbor- 
hood foci  of  fat  necrosis  were  somewhat  more  abundant 
than  in  the  former  experiments.  They  were  able,  more- 
over, to  produce  similar  lesions  in  the  immediate  neigh- 
borhood of  the  gland  by  merely  cutting  the  organ  trans- 
versely, thus  allowing  the  pancreatic  juice  free  access 
to  the  abdominal  cavity.  Hildebrand  has  maintained 
that  obstruction  to  the  outflow  of  the  secretion,  alone  or 
combined  with  occlusion  of  the  veins,  or  the  escape  of 
pancreatic  juice  into  the  peritoneal  cavity,  results  in  the 
production  of  typical  fat  necrosis  about  the  pancreas  and 
even  in  the  omentum  and  in  the  mesentery.  Both  Flex- 
ner  ^^  and  Williams  ^"^  have  confirmed  the  observations 
of  Hildebrand  and  Dettmer.  By  placing  a  ligature  about 
the  gland,  tying  the  veins  of  the  part  of  the  organ  distal 
to  the  ligature,  and  at  times  tearing  the  parenchjTiia  with 
a  sharp  hook,  they  obtained  fat  necrosis  in  a  considerable 
number  of  their  experiments. 

Milisch  ^5  attempted  to  reproduce  the  lesion  in  cats  by 
allowing  the  pancreatic  juice  to  escape  into  the  peri- 
toneal cavity.    A  section,  several  centimetres  in  length,' 
was  excised  from  the  splenic  arm  of  the  gland  near  the 
duodenum,  thus  isolating  the  remainder  of  the  splenic 


"  Flexner :  Jour,  of  Exper.  Med.,  1897,  ii,  413. 

'MVilliams:  Boston  Med.  and  Surj?.  Jour.,  1897,  cxxxvi,  345. 

"Milisch:  Inaug.  Di&s.,  Berlin,  1897. 


FAT  NECROSIS  183 

part  and  giving  its  secretion  free  access  to  the  abdominal 
cavity.  In  three  of  five  experiments,  the  excised  piece 
of  pancreas  was  left  free  in  the  j^eritoneal  cavity  and 
necroses  were  found  in  the  immediate  neighborhood  of 
the  organ  and  about  the  transplanted  tissue.  He  con- 
cludes from  his  experiments  that  fat  necrosis  may  be 
caused  by  pancreatic  juice  which  has  escaped  into  the 
abdominal  cavity. 

Oser  produced  foci  of  fat  necrosis  about  the  pancreas 
and  in  the  omentum  by  ligating  all  the  blood-vessels  of 
the  organ  and  separating  it  from  the  duodenum,  thus 
depriving  it  of  its  blood  supply.  By  completely  obstruct- 
ing the  circulation  of  part  of  the  pancreas  for  twenty 
minutes,  Blume  '^^  produced  hemorrhagic  infiltration  of 
the  tissue  and  fat  necrosis  in  the  neighborhood  of  the 
injured  parenchyma. 

A  number  of  experimenters — Hlava,  Korte,^"  Oser, 
Flexner  ^^  and  subsequent  observers — have  obtained  ne- 
crosis of  fat  by  injecting  into  the  parenchyma  of  the 
gland,  or  into  the  duct  after  opening  the  duodenum, 
various  substances, — artificial  gastric  juice,  dilute  acids 
and  alkalies,  oil,  and  other  substances, — causing  thereby 
hemorrhagic  necrosis  of  the  pancreas. 

In  the  experiments  cited  above,  conditions  have  been 
present  which  afford  an  opportunity  for  the  escape  of 
the  pancreatic  secretion  into  the  tissue  surrounding  the 
gland;  it  may  be  forced  backward  into  the  tissue  as  a 

"Blume:  Beit.  z.  wiss.  Med.,  Festseh.  z.  Naturforschervei-sam. 
in  Braunschweig,  1897,  139. 

"Korte:  Berliner  Klinik,  1896,  No.   102. 
"  Loc.  cit.,  p.  126. 


184  DISEASE  OF  THE  PANCREAS 

result  of  duct-obstruction,  or,  when  the  parenchyma  is 
injured,  gradual  diffusion  may  take  place.  Ever  since 
Langerhans  explained  the  process  which  takes  place 
within  the  fat-cells,  it  has  been  assumed  that  the  fat- 
splitting  enzyme  of  the  pancreas  is  the  active  factor  in 
producing  the  lesion.  Demonstration  of  a  fat-splitting 
enzjTue  in  the  necrotic  foci  was  made  by  Flexner.  Bits 
of  such  tissue  from  human  and  from  experimental  lesions, 
when  brought  into  contact  with  neutral  butter-fat,  were 
found  to  contain  an  enzyme  with  the  power  of  splitting 
this  fat  and  setting  free  acids  readily  recognized  by  their 
odor  and  reaction. 

Wells  has  found  that  commercial  pancreatin  injected 
into  the  peritoneal  cavity  of  dogs  produces  fat  necrosis 
but  loses  this  property  when  exposed  during  five  minutes 
to  a  temperature  of  71°  C. ;  this  temperature  destroys 
both  trypsin  and  steapsin.  Extracts  of  pancreas  which 
have  been  subjected  to  autolysis  lose  their  ability  to  split 
fat  but  still  cause  proteolysis ;  though  they  contain  tryp- 
sin they  have  lost  the  power  to  produce  fat  necrosis. 

Fat  necrosis  produced  by  experimental  methods  has 
been  limited  to  the  abdominal  fat,  and  usually  to  the 
immediate  neighborhood  of  the  pancreas.  The  wide  dis- 
tribution occasionally  observed  in  human  cases,  where 
almost  the  entire  abdominal  fat,  fat  within  the  pleural 
cavity  and  even  subcutaneous  fat,  may  be  studded  with 
necrotic  foci,  is  rarely  reproduced.  It  has  been  claimed 
(Oser)  that  alterations  so  widely  disseminated  and  at 
so  great  a  distance  from  the  pancreas  cannot  be  explained 
by  contact  with  its  secretion  and  it  has  been  suggested 
that  the  process  is  not  in  all  cases  the  same. 


FAT  NECROSIS  185 

Experimental  Fat  Necrosis. — In  experiments  which  I 
have  undertaken  ^^  it  has  been  found  possible  to  produce 
focal  necrosis  of  the  fat-tissue  as  wide-spread  as  that 
observed  in  human  cases  and  in  lower  animals.  They 
show  that  comjDlete  obstruction  to  the  outflow  of  the 
pancreatic  secretion  may  cause,  after  the  lapse  of  several 
weeks,  necrosis  of  the  fat  in  parts  far  distant  from  the 
pancreas. 

Both  pancreatic  ducts  were  ligated  in  two  places  and 
cut  between  the  ligatures.  In  the  cat,  which  was  used 
for  these  experiments,  the  main  duct  enters  the  duode- 
num with  the  common  bile  duct  and  is  readily  found. 
By  carefully  separating  the  pancreas  from  the  duodenum 
the  smaller  duct  may  be  exposed,  where  it  penetrates  the 
intestine  about  1  cm.  below  and  somewhat  to  the  left  of 
the  larger  duct.  The  operation  necessitates  little  or  no 
injury  to  the  substance  of  the  gland.  In  order  to  facili- 
tate the  penetration  of  the  secretion  into  the  fat-tissue, 
the  right  border  of  the  omentum  near  its  gastric  attach- 
ment in  several  instances  has  been  drawn  through  the 
opening  made  by  separating  the  pancreas  from  the  duode- 
num. Several  successful  experiments  will  be  described 
in  detail. 

Experiment  I. — A  full-grown  cat,  of  which  the  pancreatic  ducts 
have  been  ligated,  has  died  at  the  end  of  twenty-five  days.  The  subcu- 
taneous fat  over  the  lower  half  of  the  abdomen  and  in  front  of  the 
symphysis  pubis  is  profusely  studded  with  conspicuous  opaque,  white 
foci  of  irregular  shape,  often  2  mm.  in  diameter.  The  omentum  is  an 
almost  homogeneous  mass  of  opaque,  white,  slightly  friable  material. 

"  Contributions  to  the  Science  of  Medicine,  dedicated  to  William 
H.  Welch,  Johns  Hopkins  Hospital  Reports,  1900,  ix,  859.  The  experi- 
ments to  be  quoted  are  designated  by  the  numbers  used  in  that  article. 


186  DISEASE  OF  THE  PANCREAS 

The  fat  of  the  mesentery  of  both  the  small  and  large  intesthies  is  eon- 
verted  into  the  same  opaque,  white  material  and  the  perirenal  fat,  the 
retroperitoneal  fat,  and  masses  in  the  pelvis  on  either  side  of  the  blad- 
der show  in  large  part  the  same  transformation.  Below  the  peritoneum 
of  the  diaphragm  and  of  the  lateral  abdominal  walls  are  numerous 
slightly  raised  areas  of  similar  appearance.  The  gi-eater  part  of  the 
fat  in  the  parietal  layer  of  the  pericardium  has  a  nonnal  translucent 
appearance,  but  on  the  right  side  are  several  conspicuous  opaque,  white 
areas,  and  along  the  carotid  and  left  subclavian  arteries  are  several 
similar  foci.  The  pancreas,  of  which  the  duodenal  part  is  embedded 
in  a  homogeneous  mass  of  transformed  fat,  is  much  smaller  than  usual. 
No  growth  is  obtained  on  agar-agar  from  turbid  fluid  in  the  perito- 
neal cavity.  Microscopic  examination  of  the  opaque,  white  fat  of  the 
omentum,  subcutaneous  tissue,  and  pericardium  demonstrates  the  histo- 
logical chai'acter  of  fat  necrosis.  The  omentum  is  not  wholly  trans- 
formed, as  it  appears  to  be  upon  maeroseopical  examination,  but  about 
its  blood-vessels  is  intact  tissue.  Between  the  necrotic  material  and  the 
unchanged  fat  is  usually  seen  a  well-marked  zone  of  cell-proliferation. 
The  pancreas  shows  a  moderate  increase  of  its  interstitial  tissue. 

Experiment  II. — The  pancreatic  ducts  of  a  full-grown  cat  have 
been  ligated  in  two  places  and  cut  between  the  ligatures.  The  animal 
has  died  twenty  days  after  the  operation.  The  subcutaneous  tissue  of 
the  abdomen  is  found  to  contain  conspicuous  opaque,  white  areas,  the 
largest  of  which  are  about  2  mm.  in  diameter.  The  omentum  is  trans- 
formed into  an  almost  homogeneous  mass  of  opaque,  somewhat  friable, 
material.  The  mesenteric  fat  of  the  small  and  large  intestines,  the 
retroperitoneal  fat  and  the  surface  of  the  diaphragm  are  very  thickly 
studded  with  large,  conspicuous,  opaque,  white  areas.  In  the  parietal 
layer  of  the  pericardium  are  several  very  conspicuous  areas  of  fat 
necrosis.     The  pancreas  is  of  small  size  and  firmer  than  usual. 

Stained  eoverslip  preparations  made  from  the  peritoneal  exudate 
contain  numerous  desquamated  endotheloid  cells,  but  leucocytes  are 
almost  completely  absent,  and  bacteriai  are  not  discoverable.  A  small 
piece  of  omentum  and  a  bit  of  subcutaneous  fat  containing  opaque 
foci  were  tested  for  the  presence  of  a  fat-splitting  enzyme  and  well- 
marked  reactions  were  obtained. 


FAT  NECROSIS  187 

In  these  experiments  necrosis  involving  almost  the 
entire  omental  fat,  the  greater  part  of  the  mesenteric  fat, 
and  to  less  extent  the  fat-tissue  below  the  parietal  peri- 
toneum of  the  perirenal  region,  the  lateral  abdominal 
walls,  and  the  diaphragm,  the  fat  of  the  subcutaneous 
tissue  and  of  the  pericardium  has  followed  the  ligation 
of  both  pancreatic  ducts.  Obstruction  to  the  outflow  of 
the  pancreatic  secretion  causes  its  diffusion  into  the 
surrounding  tissue.  Although  no  colored  constituent, 
like  the  pigment  of  the  bile,  makes  the  pancreatic  secre- 
tion evident  to  the  eye,  its  presence  is  shown  by  the  in- 
jurious effects  which  it  exerts  upon  the  tissues.  Jaun- 
dice is  the  index  of  hepatic  obstruction,  whereas  fat 
necrosis  indicates  obstruction  of  the  pancreatic  ducts. 
In  accordance  with  this  relationship  to  the  pancreas,  we 
find  the  change  most  marked  in  the  neighborhood  of  the 
organ,  whereas  in  more  distant  parts,  which  may  be 
reached  by  gradual  diffusion  through  continuous  layers 
of  connective  tissue,  the  process  is  much  less  extensive. 
In  these  experiments  a  fat-splitting  enzjine,  doubtless 
that  of  the  pancreatic  juice,  has  been  found  in  the  distant 
subcutaneous  foci  as  well  as  in  the  necrotic  fat  adjacent 
to  the  pancreas. 

In  tlie  first  experiment  the  animal  died  at  the  end  of 
twenty-five  days;  in  the  second,  in  which  the  lesion  was 
somewhat  less  extensive,  in  twenty  days.  In  four  sub- 
sequent experiments  of  the  same  series  the  animal  sur- 
vived a  shorter  time,  and  presumably  less  opportunity 
was  afforded  for  diffusion  of  pancreatic  secretion.  The 
distribution  of  necrosis  was  much  less  extensive  and 
was  confined  to  the  fat  in  closer  proximity  to  the 
pancreas. 


188  DISEASE  OF  THE  PANCREAS 

In  two  experiments  in  which  death  occurred  within 
two  days  after  operation  foci  of  necrosis  were  not  demon- 
strable. A  third  cat,  with  ligated  ducts,  survived  twenty- 
five  days,  but  no  foci  of  fat  necrosis  were  found  at 
autopsy;  the  pancreas  was  diminished  in  size  and  firm 
in  consistence  and  the  main  duct  was  markedly  dilated. 
Microscopic  examination  demonstrated  the  presence  of 
advanced  chronic  interstitial  inflammation.  It  is  pos- 
sible that  induration  of  the  interstitial  tissue  consequent 
upon  chronic  inflammation  may  retard  the  diffusion  of 
the  obstructed  secretion. 

In  the  experiments,  in  which  widely  disseminated 
necrosis  followed  ligation  of  the  ducts,  the  animal  sur- 
vived, one,  twenty,  the  other,  twenty-five  days;  while 
in  several  instances,  in  which  the  animal  lived  a  shorter 
time,  less  extensive  necrosis  resulted.  If  this  difference 
may  be  explained  by  assuming  a  gradual  diffusion  of  the 
pancreatic  secretion,  stimulation  of  the  secreting  activity 
of  the  gland  after  ligation  of  its  ducts  will  hasten  the 
diffusion  and  more  rapidly  cause  necrosis  in  parts  distant 
from  the  organ.  In  order  to  test  this  hypothesis,  pilo- 
carpin,  which  has  been  shown  by  Heidenhain,^*'  Gottlieb,^^ 
and  others  to  stimulate  pancreatic  secretion,  was  ad- 
ministered to  an  animal  of  which  the  ducts  had  been 
ligated. 

ExPERiMEKT  X. — The  pancreatic  ducts  of  a  full-grown  cat  have 
been  ligated.  Pilocarpin  muriate  (0.005  Gm.)  ha.s  been  injected  sub- 
cutaneously  on  the  following  day  at  12  m.,  and  again  at  2  p.m.;  two 
days  later  the  same  dose  has  been  repeated  at  2  p.m.     On  the  following 

'°  Heidenhain :  Hermann's  Handb.  d.  Physiol.,  v,  197. 

="  Gottlieb:  Arch.  f.  exper.  Path.   u.  Phann.,  1894,  xxxiii,  261. 


FiG.5.27. — Experimental  fat  necrosis;  administration  of  pilocarpin  after  ligation  of  pan- 
creatic ducts.  Foci  of  necrosis  in  omental  and  mesenteric  fat,  in  fat  below  parietal  peritoneum, 
and  in  fat[of  parietal  pericardium  (Experiment  x.)- 


FAT  NECROSIS  189 

day,  at  11  a.m.,  the  animal  is  found  dead.  The  omentum  is  studded 
throughout  witli  conspicuous  opaque,  white  areas;  along  the  right 
border  near  the  stomach  they  are  confluent,  and  involve  almost  the 
whole  surface  (see  Fig.  27).  Similar  areas  are  thickly  scattered 
in  the(  duodenal  mesentery  near  the  pancreas,  in  the  mesenteiy  of  the 
small  and  large  intestine,  in  the  retroperitoneal  tissue,  in  the  subperi- 
toneal tissue  ujDon  the  surface  of  the  diaphragm  and  in  the  inter- 
muscular septa  of  the  abdominal  wall.  In  the  anterior  and  right  wall 
of  the  parietal  pericardium  are  scattered  opaque,  white  foci  about 
2  mm.  in  diameter.     The  pancreas  is  firm  in  consistence. 

Control. — The  operation  performed  upon  '  the  preceding  animal 
has  been  repeated  on  a  well-grown  eat,  which  has  been  killed  at  the 
end  of  four  days;  pilocarpin  has  not  been  administered.  Minute 
opaque,  white  areas  are  present  in  the  neighborhood  of  the  ligated 
duets,  in  the  omentum  near  the  pyloric  end  of  the  stomach,  and  in  the 
mesentery,  but  are  confined  to  the  immediate  neighborhood  of  the 
pancreas. 

In  order  to  test  the  ability  of  the  fully  formed  pan- 
creatic juice  to  produce  fat  necrosis  when  injected  into 
fat-tissue,  an  attempt  was  made  to  cause  the  secretion 
to  escape  directly  from  the  gland  into  the  subcutaneous 
fat.  To  accomplish  this  object  the  duodenal  part  of  the 
pancreas  with  the  ligatured  ends  of  the  ducts  were  drawn 
through  an  incision  in  the  left  rectus  muscle  and  brought 
in  contact  with  the  subcutaneous  fat-tissue.  Previous 
experiments  had  shown  that  the  ligature  in  many  in- 
stances ceased  after  a  time  to  bind  the  duct,  and  was 
found  loose  in  the  tissue ;  but  before  this  rupture  occurred 
opportunity  had  been  afforded  for  the  partial  healing 
of  the  abdominal  wound,  so  that  the  secretion,  finally  es- 
caping, was  poured  into  the  subcutaneous  fat.  The  oper- 
ation was  performed  upon  three  animals.  In  two  in- 
stances suppuration  of  the  abdominal  wound  ensued  and 
no  necrosis  of  fat  resulted. 


190  DISEASE  OF  THE  PANCREAS 

Experiment  XIII. — The  operation  previously  described  was  per- 
fonned  upon  a  full-grown  cat.  The  animal,  which  became  much  emaci- 
ated, died  twenty-seven  days  later.  Opposite  the  transiDlanted  pancreas 
is  a  cavity  in  the  subcutaneous  tissue  undermining  the  skin  for  a 
considerable  distance  to  the  left  of  the  median  line  and  containing 
thick,  viscid  material,  which  microscopically  shows  fat  globules  in 
abundance,  but  no  leucocytes.  The  cavity  has  broken  through  the  skin 
at  a  point  opposite  the  pancreas.  The  tissue  fonning  its  wall  is  very 
thickly  studded  with  in-eg-ular,  opaque,  white  areas,  which  in  many 
places  are  confluent,  forming  masses  of  homogeneous  necrotic  fat. 
Foci  of  fat  necrosis  are  widely  scattered  in  the  subcutaneous  tissue 
over  the  left  side  of  the  thorax  and  abdominal  wall,  being  most  abun- 
dant opposite  the  above-mentioned  cavity.  The  pancreas  is  diminished 
in  size  and  firm  in  consistence.  Microscopic  examination  shows  that 
the  opaque  white  tissue  has  the  histological  character  of  fat  necrosis. 

The  foregoing  experiments  show  that  the  pancreatic 
secretion  of  the  cat  escaping  from  the  pancreatic  duct 
into  the  tissue  about  the  pancreas,  causes  wide-spread 
necrosis  of  the  fat,  not  only  of  the  abdomen,  but  of  the 
subcutaneous  tissue  and  of  the  pericardium  as  well,  thus 
reproducing  the  wide-spread  dissemination  observed  in 
man.  The  extent  of  the  process  is  dependent  upon  the 
gradual  diffusion  of  the  fat-splitting  enzyme  and  corre- 
sponds in  some  degree  with  the  length  of  time  which  the 
animal  has  survived  the  operation;  stimulation  of  the 
secreting  activity  of  the  gland  hastens  this  diffusion. 
Wells  thinks  with  good  reason  that  diffusion  of  pancre- 
atic enzymes  may  occur  by  way  of  the  lymphatic  channels. 

Application  of  Experimental  to  Clinical  Observations. 
— Conditions  resembling  in  greater  or  less  degree  those 
of  the  foregoing  experiments  are  at  times  associated  with 
focal  fat  necrosis  in  human  subjects.  Occlusion  of  the 
duct  of  Wirsung  may  be  accompanied  by  necrosis  of  fat ; 


FAT  NECROSIS  191 

lesions  of  the  parenchyma  secondary  to  duct  obstruction 
are  usually  present  as  well.  Dieckhoff  ^^  records  such  a 
case  in  which  the  widened  duct  was  filled  with  concretions 
and  the  gland  was  the  seat  of  purulent  inflammation.  In 
an  autopsj^  performed  by  Prof.  Welch  in  the  pathological 
laboratory  of  the  Johns  Hopkins  Hospital  small  foci  of 
peripancreatic  fat  necrosis  were  associated  with  occlusion 
of  the  pancreatic  duct  by  numerous  calculi;  the  gland 
was  the  seat  of  chronic  inflammation.  Williams  ^^  re- 
cords a  similar  case.  Carcinoma  of  the  head  of  the 
pancreas  occluding  the  common  bile  duct — and  presuma- 
bly the  duct  of  Wirsung  as  well — was  in  a  case  of  Katz 
and  Winkler  ^^  accompanied  by  focal  fat  necrosis. 

In  several  instances  of  disseminated  fat  necrosis  gall- 
stones have  lodged  in  the  ampulla  of  Vater,  partially  or 
completely  closing  the  main  pancreatic  duct;  in  the  ab- 
sence of  hemorrhagic  necrosis,  foci  of  fat  necrosis  have 
been  produced.  Of  especial  interest  are  the  cases  re- 
ported by  Flexner  and  by  Fraenkel,^-^  in  which,  though 
disseminated  fat  necrosis  has  been  present,  no  lesion  of 
the  pancreas  is  recorded.  In  such  cases  there  can  be 
little  doubt  that  a  gall-stone  has  compressed,  the  pancre- 
atic duct. 

In  the  following  case  both  inflammation  of  the  pan- 
creas and  necrosis  of  fat  were  doubtless  due  to  the  pas- 
sage of  one  or  more  calculi  through  the  diverticulum  of 
Vater,  and  were  the  result  of  duct-obstruction,  pancreatic 

'' Dieckhoff :  Festsch.  f.  Thierf elder,  Leipzig,  1895. 
'^  hoc.  cit.,  p.  177. 

^^Katz  and  Winkler:  Die  multiple  Fettgewebsnekrose,  Berlin,  1899; 
Arch.  f.  Verdauungskr.,  1898,  iv,  289. 

"Fraenkel:    Miinchener  med.  Woch.,  1896,  xliii,  813,  844. 


192  DISEASE  OF  THE  PANCREAS 

secretion  being  forced  into  the  tissue  in  and  about  the 
gland. 

Case  VIII. — Woman,  aged  fifty  yeai-s.  Anatomical  Diagnosis. — 
Cholelithiasis  with  calculi  in  the  gall-bladder,  cystic,  hepatic,  and  com- 
mon ducts.  Adenocarcinoma  of  the  gall-bladder.  Jaundice.  Chronic 
interstitial  pancreatitis.     Peripancreatie  fat  necrosis. 

The  much-contracted  gall-bladder  and  the  hepatic  and  cystic  ducts 
are  filled  with  facetted  calculi.  The  common  bile  duct  contains  two  stones, 
each  about  1  cm.  in  diameter,  but  none  are  present  near  its  tennina- 
tion,  where  the  wall  is  somewhat  thickened  and  fibrous.  The  pancreas 
is  the  seat  of  chronic  interstitial  inflammation,  and  foci  of  fat  necrosis 
occur  in  the  neighborhood  of  the  gland. 

The  not  infrequent  association  of  fat  necrosis  and 
chronic  interstitial  pancreatitis  admits  a  similar  explana- 
tion. In  two  cases  to  be  cited  in  discussing  chronic  inter 
stitial  pancreatitis  the  two  conditions  occur,  but  are 
unaccompanied  by  any  obstruction  of  the  large  ducts. 
The  presence  of  newly  formed  contracting  fibrous  tissue 
affords  abundant  opportunity  for  the  constriction  of  the 
smaller  ducts.  In  one  of  these  cases  many  such  ducts 
on  microscopic  examination  were  found  widely  dilated 
and  filled  with  stagnant  secretion.  Local  obstruction  to 
the  outflow  of  the  pancreatic  juice  doubtless  causes  its 
diffusion  into  the  adjacent  fat,  thus  producing  foci  of 
necrosis;  but,  as  I  have  mentioned  before,  induration 
of  the  interstitial  tissue  probably  tends  to  inhibit  dis- 
semination of  the  lesion. 

In  som-C  of  the  experiments  wliich  have  been  described,' 
especially  when  the  pancreatic  ducts  have  been  trans- 
planted into  the  subcutaneous  fat,  pancreatic  juice  has 
passed  directly  from  the  duct  into  the  surrounding  tissue. 
Somewhat  similar  conditions  have  occasionally  been  ob- 


FAT  NECROSIS  193 

served  in  human  cases.  Necrosis  of  the  pancreatic  tissue 
has  in  certain  instances,  as  in  those  described  by  Chiari, 
Fraenkel,  and  Korte,  caused  such  disintegration  of  the 
organ  that  the  ruptured  duct  has  communicated  directly 
with  the  cavity  of  the  bursa  omentalis,  in  which  the  pan- 
creas has  lain.  Fat  necrosis  has  been  present  in  the 
wall  of  the  cavity,  and  usually  widely  distributed  in  the 
abdominal  fat.  The  remarkable  case  of  Chiari,  in  which 
the  pericardial  and  subpleural  fat  has  contained  foci  of 
necrosis,  belongs  to  this  group. 

In  the  majority  of  instances  widely  disseminated  fat 
necrosis  is  associated  with  hemorrhagic  necrosis  of  the 
pancreas  or  with  its  sequel,  so-called  gangrenous  pan- 
creatitis. Experimental  necrosis  produced  by  injecting 
into  the  organ  a  variety  of  substances,  of  which  the  com- 
mon character  is  an  ability  to  injure  the  parenchyma 
of  the  gland,  is  accompanied  by  similarly  disseminated 
fat  necrosis.  Here  fat  necrosis  is  the  result  of  a  lesion 
which  permits  diffusion  of  pancreatic  secretion  from  the 
injured  parenchyma  into  the  surrounding  tissue,  and  the 
same  explanation  is  applicable  to  human  cases.  Where 
hemorrhagic  necrosis  is  caused  by  a  small  calculus  lodged 
in  the  diverticulum  of  Vater,  an  additional  factor  is  in- 
volved. Since  the  calculus  occludes  the  duodenal  orifice 
of  the  duct,  secretion  from  uninjured  parts  of  the  gland 
is  dammed  back,  and  its  diffusion  into  the  surrounding 
fat  is  facilitated  by  necrosis  of  the  parenchyma.  Bile 
enters  the  pancreatic  duct  and  is  mixed  with  pancreatic 
juice.  The  wide  distribution  of  fat  necrosis  which  occurs 
in  such  cases  and  is  similarly  produced  by  experimental 
introduction  of  bile  or  bile  salts  into  the  pancreatic  duct 
of  animals  is  doubtless  due  in  part  to  the  well-known 

13 


194  DISEASE  OF  THE  PANCREAS 

power  of  bile  to  increase  the  activity  of  the  fat-splitting 
enzyme  of  the  jjancreas. 

It  has  been  claimed  that  fat  necrosis  may  occur  with- 
out lesion  of  the  pancreas,  but  none  of  the  cases  which 
illustrate  the  independent  occurrence  of  fat  necrosis  are 
described  so  completely  that  disease  of  the  gland  can 
be  excluded.  Exceptions  perhaps  are  the  unique  cases  of 
Wulff  2^  and  of  Fabyan.^^  The  following  case  has  been 
described  by  Wulff : 

A  man  forty  years  of  age  had  abdominal  pain  most  severe  in  the 
region  of  the  caecum;  incision  into  what  appeared  to  be  an  abscess 
above  Poupart's  ligament  disclosed  fat  transformed  into  wax-like  ma- 
terial. A  pure  culture  of  Staphylococcus  pyogenes  aureus  was 
obtained.  Death  occurred  as  the  result  of  hemorrhage  on  the  nine- 
teenth day  of  the  disease.  Preperitoneal  fat  of  the  abdominal  wall 
had  undergone  necrosis;  there  was  a  retrocaecal  abscess  containing 
necrotic  fat  but  the  appendix  was  normal.  The  omentum  and  mesen- 
tery contained  disseminated  foci  of  fat  necrosis  and  similar  foci  were 
present  in  the  pericardium.  The  pancreas  was  surrounded  by  fat  in 
which  were  small  foci  of  necrosis,  but  the  gland  was  normal.  The 
nature  of  the  retrocaecal  abscess  was  undetermined. 

The  exceptional  character  of  such  cases  suggests  the 
possibility  that  a  localized  lesion  of  the  pancreas  has 
escaped  notice.  An  aberrant  pancreas  in  the  wall  of  the 
small  intestine  might  explain  a  lesion  similar  to  that  just 
described ;  Warthin  ^s  has  observed  fat  necrosis  about  an 
aberrant  gland.  The  occurrence  of  fat  necrosis  produced 
by  intestinal  fluid  containing  fat-splitting  enzyme  of  the 
pancreas  cannot  be  excluded.    In  the  case  of  Fabyan  fat 


"Wulff:  Berliner  klin.  Woch.,  1902,  xxxix,  734. 

'"  Fabyan:  Bull,  of  (he  Joluis  Hopkins  TTosj).,  1007,  xviii  349. 

="  Warthin :  Phys.  and  Surg.,  1904,  xxvi,  337. 


FAT  NECROSIS  195 

necrosis  limited  to  the  subcutaneous  tissue  of  the  face 
and  elsewhere  occurred  in  a  child  fourteen  days  old; 
there  was  no  lesion  of  the  pancreas  or  intestine. 

Parapancreatic  Fat  Necrosis. — The  not  infrequent  occurrence  of 
minute  foci  of  fat  necrosis  in  and  upon  the  pancreas  was  first  noted 
by  Balser;  the  condition,  which  may  be  designated  parapancreatic 
fat  necrosis,  was  found  in  five  of  twenty  bodies  which  he  examined. 
On  account  of  their  small  size,  seldom  more  than  a  millimetre  in  diame- 
ter, and  their  limited  distribution,  they  are  frequently  overlooked,  but 
otherwise  agree  in  character  with  the  lesion  which,  owing  to  its  greater 
extent  and  distribution,  has  been  designated  disseminated  fat  necrosis. 
Langerhans  found  these  minute  foci  of  necrosis  in  four  of  twenty- 
eight  autopsies,  Chiari  twenty-three  times  in  seventy-five  autopsies, 
Williams  eight  times  in  one  hundred.  The  change  has  been  thought 
to  occur  unassociated  with  lesions  of  the  pancreas.  Langerhans  be- 
lieved that  it  might  result  from  post-mortem  action  of  the  pancreatic 
juice;  and  in  support  of  this  suggestion  Williams  states  that  the  pan- 
creatic cells  near  the  areas  of  fat  necrosis  show  evidence  of  self- 
digestion. 

The  frequent  occurrence  of  advanced  self-digestion  of  the  pan- 
creas, unaccompanied  by  any  evidence  of  fat  necrosis,  shows  that  post- 
mortem contact  with  the  pancreatic  enzymes  is  insufficient  to  produce 
the  change.  When,  moreover,  fat  removed  from  the  body  is  exposed 
to  the  action  of  pancreatic  tissue,  alterations  comparable  to  those 
associated  with  this  form  of  necrosis  do  not  occur. 

Chiari  believes  that  self-digestion  of  the  pancreas  so  frequently 
observed  at  autopsy  may  set  in  shortly  before  death,  occurring  as  an 
ante-mortem  or  agonal  change.  Extravasation  of  blood  into  the  par- 
tially digested  tissue  can  occur,  he  thinks,  only  before  death,  and  when 
present  gives  evidence  that  self -digestion  has  beg-un  ante  mortem.  Par- 
tial destruction  of  the  parenchyma  would  thus  afford  opportunity  for 
diffusion  of  fat-splitting  enzyme  into  the  surrounding  fat.  Under  such 
conditions  it  appears  probable  *^hat  fat  necrosis  may  occur,  and  in  the 
following  instance  the  lesion  has  accompanied  self -digestion  associated 
with  multiple  hemorrhages. 


196  DISEASE  OF  THE  PANCREAS 

Case  IX. — Man,  aged  fifty-three  yeai-s.  Anatomical  Diagnosis. — 
Emphysema  of  the  lungs;  hypertrophy  of  the  right  side  of  the  heart; 
chronic  passive  congestion  of  the  \iscera;  self-digestion  of  the  pan- 
creas, vrith  multiple  ecchymoses ;   parapancreatic   fat  necrosis. 

The  pancreas  is  verj'  soft,  and  in  the  interstitial  tissue  are  scat- 
tered ecchymoses.  Upon  the  surface  of  the  organ  occur  veiy  small, 
opaque,  yellow  foci  of  fat  necrosis.  Microscopic  examination  shows 
the  existence  of  advanced  self -digestion,  with  hemoiThage  here  and 
there  into  the  interstitial  tissue. 

Where  parapancreatic  fat  necrosis  occurs,  microscopic  examination 
of  the  pancreas  may  demonstrate  the  presence  of  a  well-marked  lesion 
previously  unobserved  by  the  naked  eye.  Foci  of  fat  necrosis  about 
the  pancreas  so  minut«  that  they  desen'e  the  designation  parapancreatic 
have  been  found  associated  with  chronic  interstitial  pancreatitis  in  Cases 
XIT  and  XXVII,  to  be   described  later. 

In  other  instances  it  is  not  improbable  that  minute  foci  of  necrosis 
follow  duct-obstruction,  which  presumably  has  occurred  only  a  few 
hours  before  death.  In  several  cases  which  I  have  examined  the  pan- 
creatic duct  has  been  filled  with  a  ven,'  \T.scid  secretion  containing 
niunerous  desquamated  cells.  It  appears  that  the  pancreatic  secretion 
shortly  before  death  has  undergone  a  change,  in  consequence  of  which 
it  flows  with  much  difficulty.  This  condition  has  been  described  as 
catarrhal  pancreatitis.  The  following  case  illustrates  the  association 
of  parapancreatic  fat  necrosis  with  this  change. 

Case  X. — Woman,  aged  fifty  years.  Anatomical  Diagnosis. — 
Chronic  nephritis;  large  red  kidneys.  Hypertrophy  and  dilatation 
of  the  heart ;  general  anasarca.     Parapancreatic  fat  necrosis. 

The  pancreas  is  firm  and  apparently  normal.  In  the  fat,  upon 
its  surface,  and  in  the  interstitial  tissue  are  small,  conspicuous,  opaque, 
white  areas  of  fat  necrosis.  The  duct  of  Wirsung  is  filled  with  very 
viscid,  pearly-white,  semifluid  material,  which,  examined  microscopi- 
cally, contains  columnar  epithelial  cells  in  great  quantity. 

Doubtless  the  parapancreatic  foci  of  fat  necrosis  so  frequently 
obser\ed  at  autopsy  are  referable  to  a  variety  of  conditions, — for  ex- 
ample,   to    chronic    inflammation   of   the    pancreas,    to    partial    duct- 


FAT  NECROSIS  197 

oeelusion,  and  with  much  probability  to  other  causes,  among  which 
agonal  self-digestion  of  the  pancreas  has  a  place.  Nevertheless,  in  its 
essential  features  the  lesion  resembles  more  widely  distributed  necrosis, 
and  is  produced  by  the  penetration  of  the  fat-splitting  enzyme  of  the 
pancreatic  juice  into  living  adipose  tissue. 

Clinical  Significance  of  Fat  Necrosis. — By  some 
writers  fat  necrosis  has  been  described  as  a  disease  asso- 
ciated with  certain  more  or  less  ill-defined  sjnnptoms. 
The  condition,  on  the  contrary,  is  a  consequence  of  pan- 
creatic disease  and,  it  has  been  previonsly  pointed  ont, 
bears  much  the  same  relation  to  lesion  of  the  pancreas 
as  does  jaundice  to  hepatic  disease.  Its  presence  gives 
evidence  that  the  pancreatic  secretion  has  been  diverted 
from  its  normal  channels  into  the  interstitial  tissue  of 
the  organ  and  into  the  neighboring  fatty  tissue. 

In  a  case  cited  by  Hansemann,  foci  of  necrosis 
occurred  in  the  subcutaneous  tissue,  and  their  presence 
was  marked  by  circumscribed  injection  of  the  overlying 
skin.  Rarely,  however,  does  the  lesion  affect  adipose 
tissue  outside  of  the  abdomen,  and  during  life  it  is  recog- 
nizable only  when  the  peritoneal  cavity  is  opened.  Since 
disseminated  fat  necrosis  indicates  the  existence  of  grave 
disease  of  the  pancreas,  its  recognition  is  of  importance 
to  the  surgeon  who  opens  the  abdominal  cavity.  Particu- 
larly significant  is  its  recognition  when  pancreatic  disease 
has  been  unsuspected  and  operation  has  been  undertaken, 
perhaps  with  the  purpose  of  relieving  intestinal  obstruc- 
tion suggested  by  the  symptoms  of  hemorrhagic  necrosis 
of  the  pancreas.  With  few  exceptions  disseminated  focal 
necrosis  of  fat  encountered  at  operation  gives  evidence 
that  the  pancreas  is  the  seat  of  hemorrhagic  necrosis  or 
of  secondary  gangrenous  change. 


198  DISEASE  OF  THE  PANCREAS 

Foci  of  necrotic  fat  are  conspicuous  by  reason  of  tlieir 
homogeneous,  opaque,  yellowish- white  color,  in  marked 
contrast  to  the  surrounding  translucent  yellow  fat,  and 
when  the  omentum  is  exposed  it  is  unlikely  that  they  will 
be  overlooked  if  present.  To  one  who  has  seen  the  lesion 
it  is  unmistakable,  but  to  the  inexperienced  partially 
caseous  miliary  tubercles  or  carcinomatous  nodules  un- 
dergoing necrosis  may  be  suggested  by  the  shape  and 
color  of  the  sharply  defined  areas.  The  lesion,  however, 
is  not  elevated  and  nodule-like,  but  on  examination  is 
found  to  represent  a  transformation  of  the  pre-existing 
fat. 

When  the  outflow  of  bile  is  hindered  and  jaundice 
occurs,  biliary  pigments  make  their  appearance  in  the 
urine.  Abundant  evidence  has  shown  that  fat  necrosis 
is  due  to  the  action  of  the  fat-splitting  enzyme  secreted 
by  the  pancreas,  and  the  possibility  suggests  itself  that 
the  enzyme  which  is  free  in  the  tissue  may  be  excreted 
by  the  kidneys,  though  it  is  not  improbable  that  the 
acidity  of  the  urine  may  partially  or  completely  destroy 
its  activity. 

I  have  examined  the  urine  in  one  instance  of  hemor- 
rhagic necrosis  of  the  pancreas. ^'^  The  method  employed 
is  that  described  by  Kastle  and  Loevenhart  ^" ;  ethyl 
butyrate  carefully  purified,  when  acted  upon  by  a  fat- 
splitting  enzyme,  is  decomposed  with  the  formation  of 
butyric  acid,  which  gives  an  acid  reaction  to  the  solution. 

Following  the  operation  which  was  perfonned  in  Case  V  (see 
page  148)  the  patient  voided  no  urine,  and  in  the  bladder  at  autopsy 
was  found  only  a  small  quantity.     After  adding  a  few  drops  of  a 

"•  Opie:  Bull,  of  the  Johns  Hopkins  Hosp.,  1902,  xiii,  117. 

*°  Kastle  and  Loevenhart:  American  Chem.  Jour.,  1900,  xxiv,  No.  6. 


FAT  NECROSIS  199 

solution  of  litmus,  this  urine  was  neutralized  with  potassium  hydroxide 
(one-tenth  normal  solution)  and  divided  into  two  parts.  To  one  part 
was  added  a  few  drops  of  ethyl  butyrate.  The  second  part,  used 
as  a  control,  was  boiled  in  order  to  destroy  the  enzyme,  if  present,  and 
ethyl  butyrate  was  added.  Both  specimens  were  kept  at  37°  C,  and 
at  the  end  of  twenty-four  hours  the  unboiled  specimen  had  acquired 
a  well-marked  acid  reaction,  whereas  the  control  specimen  was  un- 
changed. Owing  to  the  small  quantity  of  urine  obtained  it  was  not 
possible  to  repeat  the  test. 

Eecognition  in  the  urine  of  an  enzyme  derived  from 
the  pancreas  would  afford  a  certain  means  for  the  diag- 
nosis of  obscure  pancreatic  affections  accompanied  by 
fat  necrosis,  notably  hemorrhagic  necrosis. 

Experiments  of  Hewlett  ^^  have  shown  that  fat-split- 
ting enzyme  may  appear  in  the  urine  as  the  result  of  a 
variety  of  injuries  to  the  pancreas.  The  urine  of  normal 
dogs  contains  little  if  any  enzyme  capable  of  splitting 
ethyl  butyrate,  but  during  the  first  three  or  even  five  days 
after  ligation  of  the  pancreatic  ducts  lipolytic  enzyme  is 
demonstrable  in  the  urine.  The  same  enzyme  in  greater 
amount  is  present  after  hemorrhagic  necrosis  has  been 
produced  by  injection  of  hydrochloric  acid  or  bile  into  the 
pancreatic  duct. 

When  fat  necrosis  is  observed  at  operation  the  prog- 
nosis and  treatment  are  those  of  the  associated  pancre- 
atic disease.  I  have  cited  instances  in  which  necrosis  of 
fat  observed  at  operation  has  been  found  to  have  disap- 
peared when  the  abdomen  has  been  subsequently  opened. 
Truhart  cites  cases  in  which  focal  fat  necrosis  has  been 
observed  at  operation  and  recovery  has  occurred. 

^  Hewlett :   Jour,  of  Med.  Research,  1904,  xi,  377. 


CHAPTER  VIII. 


ACUTE    PANCREATITIS. 


The  use  of  the  term  inilammation,  to  describe  the 
peculiar  pancreatic  lesion  which  has  been  more  appro- 
priately described  as  necrosis,  has  produced  much  con- 
fusion in  the  classification  of  various  inflammatory 
changes  to  which  the  gland  is  subject.  Acute  inflamma- 
tion of  the  pancreas  does  not  differ  essentially  from  acute 
inflammation  of  the  salivary  glands,  of  the  liver,  or  of 
other  organs.  The  pancreas,  like  the  salivary  gland, 
may  exhibit  acute  interstitial  inflammation  character- 
ized by  accumulation  of  inflammatory  products  in  the 
interstitial  tissue  of  the  gland,  and  likewise  this  lesion 
usually  has  its  origin  in  the  ducts  of  the  gland.  Analogy 
with  similar  inflammation  of  other  organs  makes  it  prob- 
able that  resolution  with  recovery  may  occur,  but  when 
there  is  abundant  accumulation  of  leucocytes  solution 
of  tissue  ensues  and  an  abscess  cavity  is  formed;  acute 
interstitial  pancreatitis  is  distinguished  from  suppura- 
tive pancreatitis  by  absence  of  abscess  formation. 

In  some  instances  suppuration  occurs  in  consequence 
of  hemorrhagic  necrosis  of  the  pancreas,  hemorrhagic 
and  necrotic  tissue  being  susceptible  to  bacterial  infec- 
tion. The  occurrence  of  such  abscesses  makes  a  sharp 
separation  of  gangrene  and  suppuration  impossible. 
When  hemorrhagic  necrosis  of  the  pancreas  has  occurred, 
fluid  almost  invariably  accumulates  in  the  lesser  peri- 
toneal cavity.  With  progress  of  the  changes  which  give 
to  the  pancreas  the  appearance  well  described  as  gan- 
grene, changes  occur  in  the  mixture  of  blood,  products 

200 


ACUTE  PANCREATITIS  201 

of  pancreatic  secretion  and  necrotic  fat  which  now  fills 
the  cavity.  The  fluid  is  usually  described  as  pus,  but  how 
much  it  owes  its  peculiar  properties  to  inflammatory 
products — e.g.,  polynuclear  leucocytes, — and  how  much  to 
products — e.g.,  enzymes  derived  from  the  pancreas, — is 
doubtful.  In  many  instances  at  least  infection  and 
doubtless  true  suppuration  occurs.  In  many  recorded 
cases  these  so-called  peripancreatic  abscesses  have  been 
found  at  operation,  but  it  has  been  impossible  to  decide 
if  hemorrhagic  necrosis  or  suppurative  pancreatitis  has 
been  responsible  for  the  localized  peritonitis ;  not  infre- 
quently the  lesion  has  been  described  as  suppurative  pan- 
creatitis although  the  pancreas  itself  has  not  been 
examined. 

There  is  little  evidence  that  the  change  which  has 
been  designated  catarrhal  pancreatitis  (Curtin  ^)  is  an 
inflammatory  process.  The  pancreas  is  unusually  hard ; 
the  contents  of  the  larger  ducts  is  viscid,  and  contains 
desquamated  columnar  cells;  acini  are  considerably 
dilated.  There  is  unusually  abundant  secretion  of  mucus 
or  mucus-like  substances  derived  perhaps  from  the  small 
glands  in  the  wall  of  the  larger  ducts,  but  accumulation 
of  inflammatory  products  such  as  leucocytes  or  fibrin  is 
wanting.  Lando  ^  thinks  that  such  stagnation  of  pan- 
creatic secretion  within  the  acini  may  be  followed  by 
chronic  interstitial  pancreatitis. 

Etiology. — When  suppurative  pancreatitis  is  not 
secondary  to  hemorrhagic  necrosis  it  occurs,  doubtless 
with  few  exceptions,  as  the  result  of  ascending  infection 
by  way  of  the  pancreatic  duct.     Korte,  Carnot  and  others 

'  Curtin :  Philadelphia  Hosp.  Rep.,  1902,  v. 
'  Lando :  Zeit.  f .  Heilk.,  1906,  Hf t.  i. 


202  DISEASE  OF  THE  PANCREAS 

have  produced  pancreatic  abscess  in  animals  by  injec- 
tion of  Bacillus  coli  into  the  pancreatic  duct.  The  diver- 
ticulum of  Vater  is  provided  with  valve-like  folds  which 
prevent  entrance  of  intestinal  contents  into  the  pancre- 
atic ducts,  and  at  autopsy  it  is  not  possible  to  force 
m.aterial  from  the  duodenum  into  the  duct  of  Wirsung. 
The  flow  of  pancreatic  juice  aids  in  preventing  entrance 
of  bacteria  and  occlusion  of  the  ducts  affords  conditions 
favorable  to  their  entrance. 

Pancreatic  abscess  occurs  in  association  with  chole- 
lithiasis; occlusion  of  the  duct  of  Wirsung  by  a  biliary 
calculus  lodged  in  the  diverticulum  of  Vater  may  allow 
the  entrance  of  bacteria  particularly  when  the  bile  pas- 
sages are  the  seat  of  inflammation.  In  two  cases  of 
Mayo  Robson,  abscess  of  the  pancreas  has  accompanied 
cholelithiasis  and  suppurative  cholangeitis.  With  sup- 
purative pancreatitis  Dieckhoff  found  a  gall-stone  in  the 
duct  of  Wirsung,  which  was  dilated  to  accommodate  it. 

Of  special  interest  is  a  case  reported  by  Fuchs.^  A 
man  aged  thirty-two  years,  who  had  had  recurring  ab- 
dominal pain  and  vomiting,  suffered  during  three  months 
with  repeated  attacks  of  great  severity,  on  one  occasion 
accompanied  by  jaundice.  Operation  disclosed  the  pres- 
ence of  a  calculus  the  size  of  a  bean  situated  within  the 
diverticulum  of  Vater.  In  the  head  of  the  pancreas  was 
a  small  abscess.  Evacuation  of  the  abscess  and  removal 
of  the  calculus  were  followed  by  recovery.  Hemorrhagic 
necrosis  of  the  pancreas  may  have  preceded  the  abscess. 
Chiari  *  has  described  a  similar  case. 

'Fuehs:  Deutsche  med.  Woch.,  1902,  xxviii,  829. 

*  Chiari:  Verhand,  d.  deutschen  path.  Gesell.,  1909,  xiii,  301. 


ACUTE  PANCREATITIS  203 

Pancreatic  calculi  are  with  relative  frequency  accom- 
panied by  pancreatic  suppuration. 

Suppurative  pancreatitis  may  be  caused  by  carcinoma 
compressing  the  pancreatic  duct;  in  a  case  described  by 
Pearce  ^  carcinoma  of  the  diverticulum  of  Vater  has  been 
accompanied  by  multiple  abscesses  in  the  head  of  the 
pancreas. 

Various  micro-organisms  have  been  isolated  from 
pancreatic  abscesses;  both  cocci  and  bacilli,  including 
Bacillus  coli,  have  been  found  by  Maas,^  and  Etienne "' 
obtained  pyogenic  cocci,  Proteus  vulgaris  and  other  bac- 
teria. Dieckhoff  has  found  Diplococcus  lanceolatus  in 
two  instances  and  Bacillus  coli  in  another. 

Pathology. — The  pancreas  occasionally  exhibits  acute 
interstitial  inflammation  without  suppuration  (acute  in- 
terstitial pancreatitis).  In  the  following  case  the  inter- 
stitial tissue  of  the  gland  has  been  oedematous  and  con- 
tains pol}Tiuclear  leucocytes ;  in  the  ducts  are  leucocytes. 
It  is  not  improbable  that  ascending  inflammation  of  the 
pancreatic  ducts  has  been  secondary  to  acute  inflamma- 
tion of  the  stomach  and  duodenum. 

Case  XI. — A  woman,  aged  thirty-eight  years,  admitted  to  the 
Johns  Hopkins  Hospital,  had  suffered  during  pregnancy  a  year  before 
examination  with  swelling  of  the  feet  and  frequency  of  urination.  She 
had  had  indigestion  and  had  vomited  frequently  after  meals.  The 
urine  contained  a  considerable  amount  of  albumin,  hyaline  and  epithe- 
lial casts.  Death  occurred  with  iiraemie  coma  eighteen  days  after 
admission. 

Anatomical  Diagnosis. — Chronic  diffuse  nephritis,  small  granular 

°  Pearce :  Albany  Med.  Ann.,  1904,  xxv,  389. 

°  Maas :    Quoted  by  Etienne. 

'  Etienne :    Arch,  de  med.  exper.,  1898,  x,  177. 


204  DISEASE  OF  THE  PANCREAS 

kidneys;  hypertrophy  of  the  heart;  general  arterial  sclerosis;  chronic 
passive  congestion  of  the  viscera;  acute  and  chronic  gastritis  and 
duodenitis;  acute  interstitial  pancreatitis. 

The  stomach  contains  clear  viscid  mucus  adherent  to  the  mucosa, 
which  is  deep  scarlet-red.  In  the  duodenum,  particularly  upon  the 
summits  of  the  valvulae  conniventes,  similar  injection  is  seen.  The 
pancreas  is  very  firm. 

Microscopical  examination  shows  that  the  superficial  blood-vessels 
of  the  gastric  mucosa  are  deeply  injected;  between  and  within  the 
glands  polynuclear  leucocytes  are  present  in  large  number.  In  the 
duodenal  mucosa  the  same  changes  are  slightly  less  marked.  The  inter- 
stitial tissue  of  the  pancreas  is  oedematous  and  infiltrated  with  poly- 
nuclear leucocytes,  often  forming  collections  of  considerable  size.  The 
ducts  contain  products  of  secretion  and  polynuclear  leucocytes  in 
abundance. 

The  foregoing  case  represents  an  early  stage  of  the 
inflammatory  process  which  in  some  instances  is  followed 
by  suppuration.  The  relation  between  suppurative  pan- 
creatitis and  infection  by  way  of  the  ducts  has  been 
studied  in  five  cases  by  Dieckhoff.  The  ducts  of  the 
gland  are  dilated  and  have  lost  in  places  their  epithelial 
lining;  some  are  filled  by  clumps  of  bacteria  or  by  poly- 
nuclear leucocytes.  From  the  ducts  bacteria  enter  the 
acini,  or,  penetrating  the  wall  of  the  duct,  find  their  way 
into  the  interlobular  tissue. 

In  a  case  of  Musser  ^  the  head  of  the  pancreas  con- 
tained an  abscess  the  size  of  an  orange,  and  the  remainder 
of  the  gland,  which  was  very  hard,  contained  numerous 
smaller  abscesses.  Suppuration  may  occur  diffusely 
throughout  the  pancreas ;  in  a  case  of  Etienne  the  gland 
was  infiltrated  with  pus,  drops  escaping  from  the  cut 

'Musser:  American  Jour,  of  the  Med.  Scien.,  1886,  xei,  449. 


ACUTE  PANCREATITIS  205 

ducts.  The  organ  may  contain  communicating  cavities 
of  regular  shape,  or  numerous  isolated  abscesses  may 
occur.  When  there  is  a  single  abscess  cavity  it  is  usually 
situated  in  the  head  of  the  gland. 

Fitz  noted  the  infrequency  of  fat  necrosis  with  sup- 
purative inflammation  of  the  pancreas,  whereas  so-called 
acute  hemorrhagic  pancreatitis  was  constantly  associated 
with  fat  necrosis.  The  observation  is  equally  applicable 
to  suppurative  pancreatis  and  hemorrhagic  necrosis  pro- 
duced experimentally. 

Sequelae  of  pancreatic  abscess  are  numerous  and  dan- 
gerous. Peritonitis  affecting  the  lesser  peritoneal  cavity 
occurs  almost  constantly  and  perforation  into  the  general 
peritoneal  cavity  may  follow.  Rupture  into  the  stomach 
or  intestine  has  occurred  and  vomiting  or  discharge  from 
the  bowel  of  purulent  or  hemorrhagic  material  has  been 
described.  Thrombosis  and  infection  of  the  splenic  and 
portal  veins  may  be  followed  by  metastatic  abscess  of  the 
liver. 

Symptoms. — In  accordance  with  its  diverse  etiology 
the  sym.ptoms  of  suppurative  pancreatitis  exhibit  con- 
siderable variation.  Occurring  as  a  sequel  of  hemor- 
rhagic necrosis  of  the  pancreas,  cholelithiasis,  pancre- 
atic lithiasis  or  cyst,  its  symptoms  are  modified  by  those 
of  the  preceding  condition.  In  about  half  of  the  cases 
according  to  Korte  there  is  sudden  onset  with  intense 
epigastric  pain,  vomiting  and  collapse,  the  sjnnptoms  be- 
ing those  usually  associated  with  hemorrhagic  necrosis  of 
the  pancreas.  The  severity  of  the  symptoms  diminishes 
and  the  disease  pursues  a  chronic  course,  though  death 
within  two  or  three  days  has  been  observed  (Dieckhoff. 


206  DISEASE  OF  THE  PANCREAS 

Simon  and  Stanley  ^).  In  a  second  group  of  cases  onset 
is  gradual  and  symptoms  less  severe ;  there  is  abdominal 
pain  which  may  be  little  more  than  discomfort  and  at  the 
same  time  gastric  disturbance  occurs.  The  tendency  of 
suppurative  pancreatitis  to  take  a  chronic  course  is  illus- 
trated by  cases  of  Fitz;  in  six  instances  death  occurred 
during  the  first  month,  in  three  during  the  second  month, 
and  in  five  between  the  fourth  and  eleventh  months. 

Without  elevation  of  temperature  and  with  no  pal- 
pable mass  in  the  upper  part  of  the  abdomen,  pancreatic 
suppuration  is  not  recognizable.  Nevertheless,  in  only 
part  of  the  cases  are  these  symptoms  present;  in  many 
cases  there  is  fever,  temperature  reaching  perhaps  105° 
F.,  with  recurring  chills,  but  in  another  group  of  cases 
there  is  no  fever  and  little  to  suggest  either  suppurative 
inflammation  or  disease  of  the  pancreas.  Leucocytosis 
has  usually  been  present. 

Eecognizable  tumor  has  been  found  in  little  more  than 
a  fourth  of  the  cases  (Korte).  Since  such  a  tumor  is  due 
to  accumulation  of  inflanmiatory  products  within  the 
lesser  peritoneal  cavity,  it  does  not  differ  from  that 
associated  with  gangrene  of  the  pancreas. 

Disturbance  of  digestion  due  to  impairment  of  pancre- 
atic function  rarely  occurs;  fatty  stools  have  been  ob- 
served by  Harley,^"  and  Bragsch  and  Konig  ^^  found  im- 
paired absorption  of  fat  recognizable  only  by  chemical 
methods.  Glycosuria  has  rarely  been  associated  with 
pancreatic  suppuration ;  in  cases  of  Harley  and  of  Atkin- 


•  Simon  and  Stanley :  Lancet,  1897,  i,  1325. 

"  Harley :  Trans,  of  the  London  Path.  Soc,  1862,  xiii,  118. 

"  Brugsch  and  Konig :  Berliner  klin.  Woch.,  1905,  xlii,  1605. 


ACUTE  PANCREATITIS  207 

son  ^2  glycosuria  followed  almost  complete  destruction 
of  the  pancreas.  Jaundice  may  accompany  pancreatic 
abscess  which  occupies  the  head  of  the  gland;  jaundice 
may  be  due  to  associated  cholelithiasis.  In  a  case  cited 
by  Thayer  ^^  an  abscess  at  the  junction  of  the  head 
and  body  of  the  pancreas  compressed  the  common  bile 
duct,  causing  jaundice  of  such  intensity  that  carcinoma 
was  suspected. 

Early  occurrence  of  fever  with  chills  may  suggest 
suppurative  pancreatitis,  but  a  differential  diagnosis  be- 
tween hemorrhagic  necrosis  and  suppurative  pancreatitis 
is  mth  present  knowledge  rarely  possible,  since  the  symp- 
toms of  onset  are  often  the  same.  When  the  hemor- 
rhagic lesion  has  reached  the  stage  of  gangrene  it  is 
usually  indistinguishable  from  suppurative  pancreatitis, 
for  both  conditions  may  be  accompanied  by  abscess  lim- 
ited to  the  lesser  peritoneum.  A  chronic  course  sug- 
gests the  presence  of  suppuration. 

Treatment. — Although  hemorrhagic  necrosis  and  sup- 
purative inflammation  may  be  indistinguishable  before 
operation,  recognition  of  their  peculiarities  may  have  im- 
portance for  the  surgeon  who  has  opened  the  abdominal 
cavity.  There  may  be  suppurative  pancreatitis  with  no 
fat  necrosis;  hemorrhagic  necrosis  is  accompanied  by 
disseminated  focal  fat  necrosis.  Eecovery  may  follow 
uncomplicated  necrosis  of  the  pancreas,  whereas  with 
suppurative  inflammation  of  the  gland  operation  with 
evacuation  of  pus  is  essential  for  recovery,  and  its  early 
performance    may    prevent    the    serious    complications 

"  Atkinson :    Jour,  of  the  American  Med.  Assoc,  1895,  xxiv,  999. 
"Thayer:  American  Med.,  1902,  341. 


208  DISEASE  OF  THE  PANCREAS 

which  have  been  mentioned.  Wlien  numerous  isolated 
abscesses  are  present  operation  may  fail  to  effect  com- 
plete drainage,  since  careful  examination  of  the  entire 
pancreas  is  rarely  possible.  In  a  case  of  Gallandet  ^* 
evacuation  of  pus  with  removal  of  a  pancreatic  calculus 
was  followed  by  recovery;  in  the  case  of  Fuchs  recovery 
followed  evacuation  of  pus  and  removal  of  a  gall-stone 
from  the  diverticulum  of  Vater. 

"Gallandet:    Ann.  of  Surg.,  1899,  xxx,  232. 


CHAPTER  IX. 

CHRONIC  INTEESTITIAL  PANCREATITIS. 

The  causes  and  varieties  of  chronic  interstitial  pan- 
creatitis have  been  little  studied,  and  slight  attention  has 
been  given  to  the  classification  of  various  types.  The 
lesion  is  seldom  associated  with  such  definite  symptoms 
that  it  is  recognizable  during  life,  and  even  at  autopsy 
the  condition  is  frequently  overlooked.  Though  chronic 
inflammation  of  the  pancreas  has  not  the  importance  of 
similar  changes  in  the  liver  and  kidneys,  its  relation  to 
diabetes  mellitus  makes  it  worthy  of  detailed  considera- 
tion. Indeed,  study  of  the  lesion  has  contributed  im- 
portant facts  to  the  knowledge  of  this  disease. 

The  etiology  of  interstitial  inflammation  is  often  ob- 
scure. Chronic  pancreatitis  is  not  infrequently  second- 
ary to  changes  in  the  intestine,  the  bile  passages,  and 
the  liver.  As  with  other  glands,  there  is  more  than 
one  path  by  which  inflammatory  irritants  may  reach 
the  organ:  by  way  of  the  duct,  from  the  blood-vessels, 
and  possibly  from  the  lymphatic  vessels.  Obstruction 
to  the  outflow  of  the  secretion  of  the  gland  is  followed 
by  chronic  inflammatory  changes.  The  pancreatic  duct 
opening  with  the  common  bile  duct  upon  the  mucous  mem- 
brane of  the  duodenum  is  subject  to  ascending  infection 
both  from  the  intestine  and  from  the  biliary  passages 
when  inflamed.  Bacteria,  their  toxic  products,  and  in- 
jurious substances  taken  as  food,  reaching  the  gland  by 
way  of  the  blood,  may  cause  chronic  inflammation ;  alco- 
hol, syphilis,  and  tuberculosis  are  believed  to  produce  the 

14  209 


210  DISEASE  OF  THE  PANCREAS 

lesion.  Alterations  of  the  vessel  walls,  notably  arterial 
sclerosis,  causing  grave  disturbances  of  nutrition,  have 
the  same  result. 

Acute,  rapidly  destructive  lesions  of  the  pancreas — 
for  example,  hemorrhagic  necrosis — affect  the  various 
elements  of  the  gland  almost  simultaneously,  and  dis- 
integration of  greater  or  less  extent  results.  When  the 
organ  is  attacked  by  the  less  active  irritants  which  pro- 
duce chronic  inflammation,  the  different  histological  con- 
stituents of  the  gland  are  given  greater  opportunity  to 
exhibit  differences  in  their  ability  to  withstand  the  de- 
structive process.  The  islands  of  Langerhans  do  not 
always  show  alterations  corresponding  to  those  which 
occur  in  the  tissue  about  them,  often  persisting  though 
the  adjacent  parenchyma  is  destroyed.  Moreover,  while 
with  one  variety  of  chronic  inflammation  they  are  but 
little  implicated  in  the  sclerotic  process,  with  another  they 
may  be  markedly  affected.  It  becomes  of  interest,  there- 
fore, to  study  the  relation  of  these  bodies  to  the  various 
forms  of  chronic  pancreatitis  that  are  distinguishable. 

That  form  of  chronic  inflammation  which  occurs  dur- 
ing fetal  life,  and  is  associated  with  other  manifestations 
of  congenital  sjq^hilis,  presents  histological  features 
which  distinguish  it  from  the  chronic  pancreatitis  of  adult 
life.  It  is  a  disease  of  the  developing  organ,  and  may 
appropriately  be  considered  separately. 

VARIETIES  OF  CHRONIC  PANCREATITIS. 
Several  types  of  chronic  pancreatitis  have  been  de- 
scribed, and  with  the  experimental  demonstration  of  a 
relation  between  the  pancreas  and  carbohydrate  metabol- 
ism numerous  attempts  have  been  made  to  distinguish  a 


CHRONIC  INTERSTITIAL  PANCREATITIS  211 

variety  of  the  lesion  constantly  associated  with  diabetes 
mellitus.  A  classification  of  these  various  forms  of 
chronic  inflammation  based  upon  etiological  data,  though 
desirable,  would  be,  with  our  present  knowledge,  as  un- 
satisfactory as  a  similar  classification  of  the  varieties  of 
hepatic  cirrhosis. 

In  some  examples  of  chronic  pancreatitis  fibrous  tissue 
between  the  lobules  is  increased ;  in  others  the  interacinar 
tissue  shows  marked  proliferation;  occasionally  individ- 
ual cells  are  apparently  separated  by  strands  of  fibrous 
tissue.  Corresponding  types  of  inflammation  have  been 
described  as  interlobular,  peri-acinous,  and  monocellular. 

It  has  been  thought  that  the  increase  of  interstitial 
tissue  may  have  at  times  a  constant  relation  to  the  blood- 
vessels or  to  the  ducts,  being  due,  in  part  at  least,  to 
proliferation  of  the  connective  tissue  about  these  struc- 
tures. Lemoine  and  Lannois  ^  have  described  perivas- 
cular interstitial  pancreatitis.  From  a  study  of  four 
cases  of  chronic  inflammation  associated  with  diabetes 
they  have  thought  that  the  new  growth  of  fibrous  tissue 
has  its  origin  in  the  walls  of  the  blood-vessels.  They 
find  about  the  vessels  masses  of  sclerotic  tissue  sending 
processes  between  the  acini  and  even  separating  the 
individual  cells  (sclerose  unicellulaire).  G.  Hoppe-Sey- 
ler  2  has  described  chronic  interstitial  changes  which 
he  thinks  are  the  result  of  arterial  sclerosis.  The  paren- 
chyma, he  believes,  undergoes  degeneration  as  a  conse- 
quence of  disturbed  nutrition,  but  there  is  no  constant 
anatomical  relation  between  the  vessels  and  the  newly- 

^  Lemoine  and  Lannois :  Arch,  de  med.  exper.,  1891,  iii,  33. 

'  Hoppe-Seyler,  G. :  Deutsehes  Arch,  f .  klin.  Med.,  1893,  Iii,  171. 


212  DISEASE  OF  THE  PANCREAS 

formed  tissue.  Chronic  pancreatitis  in  a  case  described 
by  Rosenthal  ^  was  accompanied  by  what  he  regarded  as 
alterations  of  the  lymph-vessels  {lymphangitis  prolifer- 
ans),  indicative,  he  thought,  of  a  probable  syphilitic 
origin. 

In  the  instances  of  chronic  inflammation  of  the  pan- 
creas which  have  been  available  for  my  study  no  constant 
relation  has  been  discoverable  between  the  newly-formed 
tissue  and  the  veins,  arteries,  lymph-vessels,  or  ducts, 
and  there  is  no  evidence  that  the  process  has  had  its 
origin  about  these  structures. 

Two  types  of  interstitial  inflammation  are,  however, 
distinguishable.*  On  the  one  hand,  though  sclerosis  is 
never  accurately  confined  to  one  locality,  it  may  be  con- 
spicuous between  the  lobules,  the  intralobular  or  inter- 
acinar  tissue  being  little,  if  at  all,  increased.  On  the 
other  hand,  the  interlobular  tissue  may  be  only  slightly 
altered,  while  fibrous  tissue  which  replaces  the  paren- 
dhyma,  separates  individual  acini.  In  the  first  case  the 
lobulation  of  the  gland,  which  is  normally  obscure,  be- 
comes more  conspicuous,  and  wide  bands  of  sclerotic 
tissue  separate  groups  of  lobules.  The  lobules  are  finally 
invaded  in  greater  or  less  degree  by  newly-formed 
stroma,  and  often  entire  lobules  are  in  process  of  disin- 
tegration and  replacement.  With  the  second  type  of 
chronic  inflammation  the  lobulation  of  the  gland  is  not 
accentuated;  new  fibrous  tissue,  primarily  within  the 
lobule,  has  a  diffuse  character,  and  a  network  of  irregular 
fibrous  strands,  which  vary  much  in  thickness,  contains 
the  glandular  acini  in  its  meshes. 


'Rosenthal:  Zeit.  f.  klin.  Med.,  1892,  xxi,  401. 
*Opie:  Jour,  of  Exper.  Med.,  1901,  v,  397. 


CHRONIC  INTERSTITIAL  PANCREATITIS  213 

If  chronic  pancreatitis  is  well  advanced,  the  organ 
may  present  gross  appearances  characteristic  of  one  or 
other  variety  of  interstitial  inflammation.  When  the 
interlobular  tissue  is  the  seat  of  predominant  change, 
the  gland  is  hard  and  dense  and  has  a  nodular  or  granu- 
lar surface.  On  section  the  tissue  has  a  compact,  homo- 
geneous appearance,  loose  areolar  tissue  between  second- 
ary and  tertiary  lobules  having  been  replaced  by  scar-like 
sclerotic  bands.  When,  on  the  other  hand,  there  is  dif- 
fuse increase  of  the  interacinar  stroma,  the  organ  tends 
to  become  tough  rather  than  hard  and  the  surface  is 
smooth.  Not  infrequently,  however,  the  pancreas 
affected  with  either  variety  of  inflammation  may  be  so 
little  altered  that  the  lesion  is  recognized  only  upon 
microscopic  examination.  Abundant  fat  infiltrating  the 
newly-formed  tissue  between  lobules  or  acini  may  obscure 
the  gross  characters  of  both  types.  Such  fat  often  con- 
tains small  foci  of  necrosis. 

The  two  types  of  chronic  interstitial  inflammation — 
(a)  interlobular  and  (b)  interacinar — characterized  by 
the  primary  localization  of  the  lesion  present  other  histo- 
logical peculiarities.  Of  much  interest  is  the  different 
relation  which  they  bear  to  the  islands  of  Langerhans, 
and  it  is  desirable  to  study  separately  the  changes  affect- 
ing these  bodies  in  the  two  conditions. 

Chronic  Interlobular  Pancreatitis, —Sclerosis  of  the 
pancreas,  produced  by  obstruction  of  the  duct,  belongs 
to  the  interlobular  type  of  chronic  inflammation.  Its 
definite  causation  as  well  as  certain  histological  features 
serve  to  distinguish  it  from  inflammatoiy  changes,  of 
which  the  etiology  is  more  obscure.     The  pathogenesis 


214  DISEASE  OF  THE  PANCREAS 

of  the  lesion  is  not,  however,  clearly  understood.  Carnot ' 
has  summarized  the  possible  factors  which  have  a  part 
in  its  production.  Eetained  secretion,  he  believes,  has 
a  toxic  action  upon  the  parenchymatous  cells.  Obstruc- 
tion to  the  outflow  of  fluid  from  the  ducts  favors  the  en- 
trance of  bacteria  from  the  duodenum.  Carnot  suggests, 
moreover,  that  reflex  nervous  stimuli,  which  normally 
reach  the  secreting  cells,  are  no  longer  capable  of  exciting 
normal  functional  activity,  and,  deprived  of  this  influence, 
the  cells  atrophy,  as  do  muscle  fibres  after  section  of  their 
motor  nerve. 

Since  the  cells  forming  the  islands  of  Langerhans 
have  no  communication  with  the  duets  and  take  no  part 
in  producing  the  pancreatic  juice,  the  possible  factors 
mentioned  would,  if  active,  affect  primarily  the  acini  and 
only  secondarily,  if  at  all,  the  interacinar  islands. 

In  the  cases  which  I  have  studied  varying  degrees  of 
atrophy  and  sclerosis  have  followed  partial  or  complete 
occlusion  of  the  pancreatic  ducts.  The  occurrence  of 
an  active  chronic  inflammatory  process  is  shown  by  the 
presence  of  numerous  IjTuphoid  cells,  plasma  cells,  and 
eosinophiles  in  the  interstitial  tissue.  The  most  marked 
increase  of  fibrous  tissue  is  between  the  lobules,  but  acini 
with  atrophied  nuclei  and  dilated  lumina  are  not  infre- 
quently separated  by  new  tissue.  Islands  of  Langer- 
hans, however,  are  completely  unaltered. 

The  following  case  illustrates  an  advanced  stage  of 
interlobular  inflammation,  the  consequence  of  duct- 
obstruction. 


Carnot:  Recherches  sur  les  pancreatites,  Thesis,  Paris,  1898. 


im'^^^l^-  fi:- 


Fig.  28. — Chronic  interlobular  pancreatitis,  showing  cosrse  bands  of  fibrous  tissue  separating 

lobules  of  parenchyma. 


CHRONIC  INTERSTITIAL  PANCREATITIS         215 

Case  XII. — The  patient,  a  woman,  aged  sixty  years,  began  about 
one  year  before  her  death  to  suffer  with  symptoms  of  obstruction  in  the 
common  bile  duct.  At  operation  performed  by  Dr.  Halsted "  a  car- 
cinoma of  the  bile  papilla  and  diverticulum  of  Vater  was  found  and 
removed.  The  biliary  and  pancreatic  ducts  were  transplanted  into  the 
duodenum.  Subsequently  an  anastomosis  was  made  between  the  gall- 
bladder and  duodenum. 

Anatomical  Diagnosis. — Recurrent  carcinoma  of  the  duodeniun ; 
metatases  in  the  liver;  occlusion  of  the  pancreatic  duct;  chronic  inter- 
stitial pancreatitis;  biliary  fistula. 

Pancreas. — On  the  left  lateral  wall  of  the  duodenum  is  a  crater- 
like  ulcer  with  raised  edges  abutting  upon  the  head  of  the  pancreas. 
The  pancreatic  duct  is  included  in  the  carcinomatous  tissue  at  the  base 
of  the  ulcer.  The  duet  is  greatly  dilated  and  the  pancreas  is  small 
and  sclerotic. 

Microscopic  Examination. — The  parenchyma  of  the  head  and  body 
has  been  almost  completely  replaced  by  dense  fibrous  tissue  which 
contains  fat  in  considerable  quantity.  Small  isolated  masses  of  glandu- 
lar tissue  still  persist  and  are  subdivided  into  lobules  by  penetrating 
strands  of  fibrous  tissue.  The  stroma  is  in  great  part  very  dense  and 
poor  in  ceils.  The  small  duets  are  dilated.  The  persistent  glandular 
tissue  is  in  part  normal  in  appearance,  but  in  other  situations  is  under- 
going disintegration,  and  the  connective  tissue  not  infrequently  marks 
out  areas  which  correspond  apparently  to  lobules,  but  contain  only  a 
few  atrophied  acini  composed  of  flattened  cells  about  a  dilated  lumen. 
Here  the  inflammatory  process  is  active;  the  connective  tissue  separat- 
ing the  atrophic  acini  is  very  cellular  and  contains  many  lymphoid 
cells,  plasma  cells,  and  eosinophiles. 

Islands  of  Langerhans,  more  abundant  in  the  tail  and  body  than 
in  the  head,  are  almost  unaltered  and  are  not  invaded  by  the  newly- 
formed  fibrous  tissue  which  surrounds  them  and  isolates  the  much 
changed  acini.  (Fig.  29.)  About  an  unaltered  island  may  be  found 
only  a  few  acini  to  indicate  that  it  was  formerly  embedded  in  the 
parenchyma,  while  elsewhere  in  the  dense  fibrous  bands  are  seen  isolated 

*  The  history  of  this  case  is  described  by  Dr.  Halsted  in  the  Bulle- 
tin of  the  Johns  Hopkins  Hospital,  1900,  xi,  4. 


216  DISEASE  OF  THE  PANCREAS 

structures  of  which  the  cells  do  not  differ  in  character  or  arrangement 
from  those  of  the  interacinar  islets.  Such  islands,  though  surrounded 
by  sclerotic  tissue,  are  not  invaded  by  it,  and  their  cells,  which  are 
normal  in  appearance,  form  columns  separated  by  delicate  capillary 
vessels. 

These  isolated  islands,  however,  finally  undergo  degenerative 
changes.  They  are  diminished  in  size  and  often  distorted.  The  cells, 
particularly  at  the  periphery',  crowded  together,  become  smaller,  and 
their  nuclei,  also  smaller  than  usual,  are  often  irregular  in  shape  and 
deeply  stained.  Further  changes  are  followed  with  difficulty,  since 
the  much  altered  gi'oups  of  cells  are  hardly  recognizable  as  islands  of 
Langerhans.  Small  groups  of  epithelial  cells,  separated  by  strands 
of  connective  tissue,  probably  represent  a  late  stage  of  atrophy  which 
precedes  their  final  disappearance  and  replacement  by  fibrous  tissue. 

When  advanced  chronic  pancreatitis  has  followed  ob- 
struction of  the  ducts,  the  organ  is  densely  sclerotic, 
glandular  tissue  having  been  replaced  in  very  large  part 
by  fibrous  stroma.  Small  masses  of  relatively  well-pre 
served  parenchyma,  little  if  at  all  invaded,  are  embedded 
in  fibrous  tissue  which  contains  almost  no  epithelial  ele- 
ments. Areas  are  seen  where  disintegration  of  the  glan- 
dular substance  is  in  active  progress,  and  here  lymphoid 
cells  are  present  in  large  numbers.  A  striking  feature 
of  the  process  is  the  abundance  of  plasma  cells  of  Unna, 
with  which  are  many  cells  containing  eosinophilic 
granulations. 

The  scattered  acini  show  atrophic  changes  similar  to 
those  previously  described.  The  islands  of  Langerhans 
which  occur  in  this  altered  glandular  tissue  are  un- ' 
changed,  and,  even  though  the  neighboring  acini  are 
widely  separated  by  inflammatory  new  growth,  are  unin- 
vaded  (Fig.  29).  The  secreting  tissue  about  them  finally 
disappears,  and  they  remain  completely  isolated  in  the 


Q^. 


8,'    ■  9--  --^S  ■■ 


•-0 


-  J    ^ 


Fig.  29. — Chronic   interlobular  pancreatitis  following  duct-obstruction    (Case  XII),   showing 
islands  unchanged  though  embedded  in  sclerotic  tissue. 


Fio.  30. — Chronic  interacinar  pancreatitis  showing  diffuse  distribution  of  newly-formed  fibrous 
tissue  and  sclerosis  of  islands  of  LaiiKerhans  (drawn  with  low  power  of  microscope). 


^J 


%e 


**1 


/*r 


4     V*'»»' 


Fig.  31. — Chronic  interstitial  pancreatitis  of  interacinar  type  (Case  XIV),  showing  tlie  invasion  of 
an  island  of  Langerhans  by  the  inflammatory  process  (drawn  with  high  power  of  microscope) . 


Fig.  32. —  l-ipomatosis 


CHRONIC  INTERSTITIAL  PANCREATITIS         217 

stroma,  not  infrequently  the  only  vestiges  of  parenchy- 
matous tissue  in  wide  sclerotic  bands.  In  a  section  from 
such  an  area  these  isolated  islands  of  Langerhans  may  be 
very  numerous;  and  since  the  sclerotic  tissue  occupies 
less  space  than  the  acini  which  it  has  replaced,  they  ap- 
pear to  be  much  more  abundant  than  in  the  normal 
glandular  parenchyma. 

In  animals,  after  experimental  ligation  of  the  ducts, 
the  islands  of  Langerhans  show  the  same  resistance  ob- 
served in  human  cases.  Schultze ''  tied  a  ligature  tightly 
about  the  pancreas  in  guinea-pigs,  and  found  that  though 
the  secreting  parenchyma  distal  to  the  ligature  under- 
Avent  inflammatory  atrophy,  islands  of  Langerhans  per- 
sisted unaltered  in  the  newly-formed  stroma.  Ssobolew,^ 
in  a  large  number  of  experiments  performed  on  rabbits, 
dogs,  and  cats,  obtained  similar  results.  In  the  pan- 
creas of  a  rabbit  which  lived  four  hundred  days  after 
operation,  fibrous  stroma  about  the  pancreatic  duct  con- 
tained, he  states,  only  islands  of  Langerhans ;  similar  ob- 
servations have  been  made  by  Sauerbeck,^  Zunz  ^^  and 
others.  Absence  of  sclerosis  noted  in  the  dog  by  U.  Lom- 
broso  ^^  is  explained  by  failure  to  occlude  both  pancre- 
atic ducts  or  by  regeneration  of  the  duct  after  ligation 
and  even  after  section  (Visentini^^). 

As  it  is  improbable  that  the  vessels  supplying  the 

'  Sclmltze :    Arch,  f .  mik.  Anat.,  1900,  Ivi,  491. 

'Ssobolew:  Cent.  f.  allg.  Path.  u.  path.  Anat.,  1900,  xi,  202; 
Virehow's  Arch.,  1902,  clxviii,  91. 

"  Sauerbeck :    Verhandl.  d.  deutschen  path.  Gesell.,  1904,  vii,  217. 

"  Zunz  and  Mayer :  Bull,  de  I'Acad.  roy.  de  med.  de  Belgique, 
1905,  xix,  509. 

"  Lombroso,  U. :    Jour,  de  physiol.  et  de  path,  gen.,  1905,  xvii,  3. 

"  Visentini :  Virehow's  Arch.,  1909,  cxcv,  555. 


218  DISEASE  OF  THE  PANCREAS 

islands  with,  blood  remain  entirely  unchanged  in  the  in- 
durated stroma,  it  can  hardly  be  doubted  that  the  nutri- 
tion of  their  cells  suffers.  The  new  tissue,  growing  older, 
apparently  contracts  and  compresses  them;  their  cells 
become  smaller,  the  nuclei  are  small,  irregular,  and  stain 
deeply.  Such  interacinar  islands  finally  disappear,  be- 
ing replaced  by  fibrous  tissue,  which  may  contain  an  occa- 
sional isolated  group  of  much  atrophied  cells,  or  may  be 
completely  devoid  of  such  structures. 

The  islands  of  Langerhans  (Fig.  29)  resist  the  scle- 
rotic process  which  follows  the  damming  back  of  secretion 
upon  the  gland,  and  finally  suffer  only  when  the  acini  are 
almost  entirely  destroyed  and  replaced  by  dense  scar-like 
tiwssue.  Not  concerned  in  the  production  of  the  pan- 
creatic juice,  they  are  not  exposed  to  its  injurious  action 
when  its  outflow  is  obstructed.  The  changes  which  com- 
pletely isolated  islands  finally  undergo  are,  it  appears, 
due  to  obliteration  of  blood-vessels  and  compression  of 
cells  by  the  contracting  scar-like  tissue  in  which  they  are 
embedded;  when  the  acini  are  replaced  by  interstitial 
tissue,  the  network  of  vessels  within  the  island,  which 
freely  anastomoses,  with  the  adjacent  capillaries,  is,  as 
the  process  advances,  less  freely  supplied  with  blood. 

Chronic  interlobular  pancreatitis  may  be  the  result 
of  some  condition  other  than  duct-obstruction.  Ascend- 
ing infection  along  the  pancreatic  duct  is  associated  with 
alterations  similar  to  those  just  described.  Secreting 
acini  in  places  atrophy  and  disappear,  but  the  islands  of 
I^angerhans  maintain  to  the  process  the  same  relation 
which  is  observable  when  the  lesion  follows  occlusion 
of  the  duct,  and  though  neighboring  acini  have  under- 
gone degenerative  changes,  islands  of  Langerhans  re- 


CHRONIC  INTERSTITIAL  PANCREATITIS         219 

main  unaltered.  Since  the  ducts  do  not  penetrate  them 
they  are  less  exposed  to  the  action  of  irritants  which 
reach  the  gland  by  way  of  the  duct. 

Chronic  Interacinar  Pancreatitis. — The  type  of  pan- 
creatitis which  may  be  conveniently  designated  "inter- 
acinar" is  characterized  by  the  presence  of  newly-formed 
tissue  within  the  lobules  (Fig.  30).  The  lesion  is  diffuse 
but  somewhat  irregular  in  distribution;  at  one  point 
there  may  be  thickening  of  the  connective-tissue  network 
supporting  the  acini,  while  elsewhere  occur  compact 
bands  or  small  masses  of  stroma.  Though  the  inter- 
lobular tissue  is  not  wholly  unaffected  by  the  inflamma- 
tory change,  its  proliferation  is  an  inconstant  and  incon- 
spicuous feature  of  the  histological  picture.  Lobulation 
of  the  gland  is  not  accentuated,  as  with  the  interlobular 
type,  but,  on  the  contrary,  the  interlobular  bounda- 
ries are  obscured  by  masses  and  strands  of  new  tissue 
within  the  lobules.  This  type  is  much  less  common  than 
the  perilobular  form,  and  has  occurred  in  only  nine  of  my 
thirty  cases.  One  of  these  has  been  associated  with  the 
condition  of  general  pigmentation  to  which  Von  Reckling- 
hausen has  given  the  name  hsemochromatosis,  and,  differ- 
ing slightly  from  the  other  cases,  it  will  be  considered 
subsequently.     The  following  cases  exemplify  the  lesion: 

Case  XIII. — Clinical  History. — The  patient,  a  man  aged  forty-nine 
years,  gave  no  history  of  alcoholic  excess.  The  present  illness  began 
twenty  months  before  death  with  polyuria  and  loss  of  weight.  A  year 
and  a  half  before  death  the  spleen  was  palpable,  and  haematemesis 
occurred  at  intervals.  At  this  time  the  imne  contained  3.5  to  3.8  per 
cent,  of  sugar.  The  patient  was  readmitted  to  the  hospital  four  days 
before  his  death  with  ascites  and  dilated  superficial  abdominal  veins. 
The  urine  contained  2.5  per  cent,  of  sugar. 


220  DISEASE  OF  THE  PANCREAS 

Anatomical  Diagnosis. — Chronic  interstitial  pancreatitis;  cirrhosis 
of  the  liver.  Thrombosis  of  the  portal,  splenic,  and  mesenteric  veins; 
hemorrhagic  infarction  of  the  intestine.  Acute  serofibrinous  and 
purulent  peritonitis;  acute  splenic  tumor. 

Pancreas. — The  organ  is  small  and  firm  in  consistence. 

Microscopic  Examination. — The  interstitial  tissue  is  greatly  in- 
creased and  is  richly  infiltrated  with  fat.  Almost  every  acinus  is  in 
greater  or  less  degree  suiTounded  by  fibrous  tissue,  but  the  lobulation 
of  the  parenchyma  is  not  more  distinct  than  usual.  In  many  places 
the  glandular  tissue  of  a  limited  area  is  almost  completely  replaced, 
^eing  represented  only  by  widely  separated  atrophic  acini.  The  new 
growth  of  tissue,  which  is  often  conspicuous  about  the  ducts  and  blood- 
vessels, bears  no  constant  relation  to  these  structures. 

Islands  of  Langerhans  are  very  abundant,  and  are  sharply  out- 
lined by  fibrous  tissue,  which  is  concentrically  aiTanged,  and  forms 
coarse  capsules,  separating  islands  of  Langerhans  from  adjacent  acini. 
There  is,  moreover,  proliferation  of  the  connective  tissue  within  these 
structures ;  along  the  capillaries  irregular  spindle-shaped  nuclei  are  more 
numerous  than  usual,  and  there  are  thickened  fibrous  strands.  The 
cells  of  the  islands  are  often  very  small,  and  their  nuclei,  diminished 
in  size,  stain  deeply;  they  are  closely  packed  together  to  form  wide, 
irregular  columns.  Not  infrequently  the  interaeinar  fibrous  tissue  is 
much  more  abundant  in  the  immediate  neighborhood  of  the  islands 
than  elsewhere,  and  here  forms  a  close  network  of  coarse  strands  with 
small  meshes  containing  atrophied  acini. 

Case  XIV. — Clinical  History. — The  patient,  a  man,  aged  forty- 
seven  years,  has  used  alcohol  in  excess.  His  health  has  been  good 
until  six  months  before  death  and  he  has  lost  little  weight.  For  three 
months  symptoms  of  diabetes  mellitus  have  been  present.  The  patient 
was  in  the  hospital  five  days  preceding  his  death,  during  which  time 
the  urine  contained  from  O.G  to  2.46  per  cent,  of  sugar;  acetone  was 
present.     He  was  dull,  drowsy  and  at  times  delirious. 

Anatomical  Diagnosis. — Chronic  interstitial  pancreatitis;  cirrhosis 
of  the  liver;  chronic  passive  congestion  of  the  spleen;  ascites.  Para- 
pancreatic  fat  necrosis.     Arterial  sclerosis;  gangrene  of  the  leg. 

Pancreas.— The   organ,   weighing   108   Gm.,   is   firm,   particularly 


CHRONIC  INTERSTITIAL  PANCREATITIS         221 

at  its  siDlenic  end.  Here  lobulation  is  obscured  and  the  texture  of  the 
gland-tissue  is  compact.  In  the  fat  within  and  about  the  organ  are 
small,  opaqv;e,  yellowish-white  areas. 

Microscopic  Examination. — Throughout  the  organ  there  is  an  abun- 
dant diffuse  new  growth  of  interstitial  tissue  between  the  individual 
acini.  The  new  tissue  is  poor  in  cells,  and  consists  in  great  part  of 
white  fibres  loosely  packed  together.  In  the  meshes  of  the  irregular 
network  which  it  forms  lie  acini,  or  small  groups  of  acini,  which  are 
often  atrophic  in  appearance.  Acini  of  large  size,  containing  many 
centro-aeinar  cells,  are  seen. 

Islands  of  Langerhans  are  abundant  in  the  tail,  and  are  of  large 
size.  They  are  frequently  surrounded  by  a  thick  capsule  of  fibrous 
tissue,  and  are  invaded  by  the  new  tissue,  which  often  forms  coarse 
ingrowths  along  their  capillaries  (Fig.  31).  Though  all  the  islands 
are  suiTounded  by  dense  sclerotic  tissue,  some  are  only  slightly  invaded. 
Where  marked  thickening  occurs  about  their  capillary  vessels,  the 
epithelial  cells  are  diminished  in  size  and  are  closely  packed  together; 
the  nuclei  are  small  and  stain  deeply. 

While  with  the  interlobular  type  of  chronic  interstitial 
inflammation  the  islands  of  Langerhans  are  unaffected 
by  the  sclerosis  and  show  changes  only  when  the  lesion 
has  reached  a  very  advanced  stage,  in  the  cases  just 
recorded  a  new  growth  of  tissue  within  the  lobules  and 
between  the  acini  invades  the  interacinar  islands.  The 
latter  are  almost  constantly  surrounded  by  fibrous  tissue, 
which  forms,  as  it  were,  a  capsule  separating  them  from 
adjacent  acini,  which  are  themselves  abnormally  sepa- 
rated from  one  another.  About  the  capillaries  of  the 
island  there  is  proliferation  of  interstitial  tissue  forming 
coarse  strands  between  the  columns  of  cells. 

With  chronic  pancreatitis  of  the  interlobular  type 
proliferation  of  interstitial  tissue  occasionally  occurs  be- 
tween the  acini,  but  is  usually  confined  to  the  periphery 


222  DISEASE  OF  THE  PANCREAS 

of  the  lobule.  The  islands  of  Langerhans,  situated  in 
the  midst  of  the  secreting  tissue,  often  near  the  centre 
of  more  or  less  clearly  defined  lobules,  are  surrounded 
by  the  least  changed  acini.  With  the  interacinar  type 
of  sclerosis  the  condition  is  different;  in  the  immediate 
neighborhood  of  the  island  is  found  the  greatest  pro- 
liferation of  fibrous  stroma,  and  the  acini,  separated 
from  it  and  from  one  another  by  coarse  strands  of  white 
fibrous  tissue,  are  more  atrophic  than  those  at  a  greater 
distance.  When  the  inflammatory  process  affects  pri- 
marily the  periphery  of  the  lobule  and  progresses  to- 
wards the  centre,  the  islands  are  affected  only  when  the 
lesion  is  very  advanced;  but  when  the  change  occurs 
diffusely  within  the  lobule,  all  parts  are  equally  affected, 
and  the  isfands  suffer  in  common  with  the  acini.  Indeed, 
it  often  appears  that  the  favorite  seat  of  the  lesion  is 
the  immediate  neighborhood  of  these  bodies. 

Localization  of  the  lesion  especially  in  the  islands  of 
Langerhans  is  well  illustrated  by  certain  cases  in  which 
an  early  stage  of  the  change  is  represented  by  accumu- 
lation of  lymphoid  cells  in  and  about  these  structures. 
Schmidt  ^^  described  a  case  of  diabetes  mellitus  in  which 
small  round  cells  were  collected  almost  exclusively  about 
the  islands  of  Langerhans ;  in  some  of  these  bodies  there 
were  thickened  strands  of  connective  tissue.  In  five  of 
the  cases  of  diabetes  studied  by  Cecil,  islands  of  Langer- 
hans have  exhibited  both  infiltration  with  lymphoid  cells 
and  sclerosis.  The  cells  are  often  numerous  within  the 
island  which  is  otherwise  apparently  normal  and  form 
a  halo  about  it;  in  the  same  gland  various  stages  may 

"  Schmidt :  Miinehener  med.  Woch.,  1902,  xlix,  51. 


CHRONIC  INTERSTITIAL  PANCREATITIS         223 

represent  a  transition  from  this  condition  to  advanced 
sclerosis  of  the  interacinar  islands,  with  formation  of 
dense  strands  of  connective  tissue  poor  in  cells. 

In  a  few  instances  an  inflammatory  process  similar  to 
that  which  with  interacinar  pancreatitis  affects  islands 
of  Langerhans  and  secreting  parenchyma  has  been  wholly 
or  almost  wholly  limited  to  the  islands  of  Langerhans. 
Such  lesions  have  been  observed  in  association  with 
diabetes  mellitus  by  Sauerbeck  ^^  and  Cecil.^^  In  four 
cases  of  Cecil  there  was  sclerosis  limited  to  the  islands 
of  Langerhans,  and  in  one  instance  there  was  in  addition 
infiltration  of  the  same  structures  with  lymphoid  cells. 

Lipomatosis. — The  interstitial  tissue  of  the  pancreas 
contains  fat  which  in  corpulent  individuals  may  form 
conspicuous  septa  continuous  with  fat  surrounding  the 
gland.  In  some  instances  fat  is  greatly  increased  and 
replaces  the  parenchymatous  tissue  of  the  organ;  the 
condition  has  been  designated  lipomatosis.  A  mass  of 
adipose  tissue  may  occupy  the  position  of  the  pancreas, 
and  glandular  tissue  is  recognizable  only  when  the  cut 
surface  of  this  fat  is  carefully  examined;  scattered  par- 
ticles of  firm,  yellowish-white  parenchyma  one  or  two 
millimetres  across  are  embedded  in  fat  and  collected  in 
clusters  about  the  ducts  of  the  gland.  Microscopic  ex- 
amination (Fig.  32)  shows  that  fat-cells  occur  between 
the  acini,  and,  as  the  process  advances,  separate  groups 
of  acini  or  individual  acini  from  their  neighbors.  Whole 
lobules  are  replaced  by  fat,  but  islands  of  Langerhans 
survive  for  a  time  and  may  persist  in  masses  of  fat 

"  Loc.  cit. 

"  CeeU :  Jour,  of  Exper.  Med.,  1909,  xi,  266. 


224  DISEASE  OF  THE  PANCREAS 

containing  no  secreting  acini.  Islands  of  Langerhans 
finally  disappear. 

Such  infiltration  with  adipose  tissue  occurs  in  asso- 
ciation with  chronic  interstitial  inflammation.  Under 
certain  conditions,  which  are  not  understood,  newly- 
formed  connective  tissue  is  occupied  by  fat;  the  lesion 
is  analogous  to  the  fatty  infiltration  which  accompanies 
atrophy  of  voluntary  muscle.  Both  interlobular  and  in- 
teracinar  types  of  chronic  pancreatitis  are  accompanied 
by  lipomatosis.  With  interlobular  pancreatitis  follow- 
ing obstruction  of  ducts  by  calculi  there  may  be  advanced 
lipomatosis.  The  lipomatosis,  which  is  not  infrequently 
found  with  diabetes  mellitus,  usually  accompanies  inter- 
acinar  pancreatitis.  In  three  of  ninety  cases  of  diabetes 
described  by  Cecil  advanced  lipomatosis  occurred  in  asso- 
ciation with  interacinar  pancreatitis,  whereas  in  many 
other  instances  the  pancreatitic  stroma  contained  a  con- 
siderable quantity  of  fat. 

Lipomatosis  occurring  with  obesity  has  been  attrib- 
uted to  excessive  use  of  alcohol.  The  change  is  not 
always  associated  with  obesity,  and  may  occur  in  emaci- 
ated individuals  (Dieckhoff,  Kasahara,  Lepine  and 
CorniP«). 

ETIOLOGY. 

Elsewhere  I  have  classified  cases  of  chronic  inter- 
stitial pancreatitis  studied  in  the  pathological  laboratory 
of  the  Johns  Hopkins  Hospital.^^  Clinical  records  were 
obtainable,  and  in  every  instance  material  was  preserved 


"  Lepine  and  Comil :  Compt.  rend.  Soc.  de  biol.,  1874,  6  ser.,  i,  372. 
"  Opie :  The  Canses  and  Varieties  of  Chronic  Interstitial  Inflam- 
mation, American  Jour,  of  the  Med.  Scien.,  1902,  cxxiii,  845. 


CHRONIC  INTERSTITIAL  PANCREATITIS         225 

for  microscopic  examination.  Of  thirty  cases,  seven- 
teen occurred  in  males  and  thirteen  in  females.  The  age 
of  the  affected  individuals  was  as  follows : 

10  to  20  years 1  case 

20  to  30  years 2  cases 

30  to  40  years 2  cases 

40  to  50  years 9  cases 

50  to  60  years 11  cases 

60  to  70  years 3  cases 

70  to  80  years 2  cases 

Twenty  cases,  more  than  two-thirds  the  total  number, 
occurred  between  the  ages  of  forty  and  sixty  years. 

Obstruction  of  the  Pancreatic  Ducts. — In  ten  cases 
chronic  interlobular  pancreatitis  was  the  result  of  duct- 
obstruction.  Ligation  of  the  duct  in  animals  is  followed 
by  chronic  inflammation ;  in  human  cases  partial  or  com- 
plete occlusion  may  be  caused  by  pancreatic  calculi  within 
the  duct  of  Wirsung,  by  biliary  calculi  within  the  adja- 
cent terminal  part  of  the  common  bile  duct,  or  by  new 
growths,  usually  carcinomata,  compressing  or  invading 
the  gland. 

In  human  cases  conditions  which  produce  obstruction 
of  the  pancreatic  duct  are  usually  such  as  favor  infec- 
tion. The  pancreas,  it  has  been  shown,  is  provided  with 
two  ducts  which,  in  nine  of  ten  instances,  anastomose 
within  the  gland.  The  duct  of  Santorini  is  occasionally 
of  large  size,  in  about  one  of  ten  cases  even  larger  than 
the  duct  of  Wirsung,  and  its  duodenal  orifice  is  freely 
patent.  In  most  subjects,  however,  the  duct  is  in  part 
rudimentary,  and  its  orifice  is  too  minute  to  act  as  an  out- 
let for  the  entire  pancreatic  secretion  should  the  duct  of 
Wirsung  be  occluded. 

15 


2^6  DISEASE  OF  THE  PANCREAS 

Pancreatic  Calculi. — Two  cases  (Cases  XXVI  and 
XXVII)  illustrate  the  advanced  grade  of  sclerosis  which 
may  follow  the  presence  of  calculi  within  the  pancreatic 
ducts.  The  lesion  derives  importance  from  the  fact  that 
diabetes  mellitus  occasionally  accompanies  chronic  in- 
flammatory changes  due  to  the  presence  of  calculi. 

Biliary  Calculi. — Riedel  ^^  has  directed  attention  to 
the  fact  that  induration  of  the  head  of  the  pancreas,  at 
times  observed  during  operations  undertaken  for  the 
removal  of  gall-stones,  may  readily  be  mistaken  for 
malignant  growth.  Carcinoma  of  the  pancreas  was  sus- 
pected in  three  of  one  hundred  and  twenty-two  such 
operations,  but  the  subsequent  history  of  these  three 
patients  disproved  this  supposition,  and  chronic  pancrea- 
titis was  found  in  one  who  died. 

Mayo  Robson  ^'^  (1900)  has  described  two  similar 
cases,  in  one  of  which  chronic  inflammation  was  demon- 
strated at  autopsy,  while  in  the  second  malignant 
growth  was  excluded  by  recovery  of  the  patient. 
In  subsequent  publications  ^^  he  has  collected  many 
similar  instances  and  believes  that  there  is  evidence 
of  chronic  pancreatitis  in  60  per  cent,  of  patients  in 
whom  operation  has  shown  the  presence  of  stone  in  the 
common  bile  duct.  The  consistency  of  the  pancreas 
varies  considerably  and  demonstration  of  chronic  inflam- 
mation at  operation  is  often  uncertain.  In  18.6  per  cent, 
of  two  hundred  and  eighty-six  operations  on  the  common 
and  hepatic  ducts  cited  by  W.  J.  Mayo  ^i  there  was  such, 

"  Riedel :  Ueber  entzundliche  Verj^rosserung-en  des  Pankreaskopfes, 
Berliner  klin.  Woeh.,  1896,  xxxiii,  1,  32. 
"  Mayo  Robson :  Lancet,  1900,  ii,  235. 
"°  See  Mayo  Robson  and  Cainmidge,  loc.  cit.,  p.  viii. 
'"Mayo:    Jour,  of  the  American  Med.  Assoc,  1908,  1,  1161. 


CHRONIC  INTERSTITIAL  PANCREATITIS         227 

definite  induration  and  enlargement  of  the  head  of  the 
pancreas  that  no  doubt  was  entertained  concerning  th6 
diagnosis,  whereas  the  same  change  occurred  in  only 
4.45  per  cent,  of  instances  with  disease  limited  to  the  gall-; 
bladder. 

The  following  case  illustrates  the  relation  of  chronic 
interlobular  pancreatitis  to  cholelithiasis  and  demon- 
strates a  mechanism  by  which  the  change  is  produced. 

Case  XV. — The  patient,  a  man,  aged  sixty-three  years,  after  re- 
peated attacks  of  jaundice  underwent  operation,  but  on  account  of 
dense  adhesions  it  was  not  possible  to  explore  the  bile  passages.  Symp- 
toms of  cirrhosis  subsequently  developed,  and  the  abdomen  was  tapped 
several  times.  The  urine  did  not  contain  sugar.  The  patient  had 
used  alcohol  in  excess. 

Anatomical  Diagnosis. — Cholelithiasis;  contraction  of  the  gall- 
bladder; calculus  in  the  common  bile  duct;  dilatation  of  bile  ducts; 
cirrhosis  of  the  liver;  chronic  interlobular  pancreatitis;  serofibrinous 
peritonitis;  chronic  nephritis;  arterial  sclerosis;  diverticula  of, 
duodenum.  [ 

The  common  bile  duct  is  greatly  dilated  and  enters  the  duodenum 
beside  a  small  diverticulum  of  the  intestinal  mucosa.  Near  its  termina- 
tion, but  just  above  its  junction  with  the  duct  of  Wirsung,  is  a  large, 
oval  gall-stone,  firmly  wedged  into  the  common  duct  in  such  a  position 
as  to  eompi-ess  the  terminal  part  of  the  pancreatic  duet,  which,  as  it 
enters  the  diverticulum  of  Vater,  passes  immediately  below  the  stone.' 
(See  Fig.  33.)  The  pancreas  is  firm  in  consistence  and  compact  in 
texture  and  microscopic  examination  shows  chronic  interlobular  pancrea- 
titis.   The  papilla  of  the  duct  of  Santorini  is  not  demonstrably  patent. 

A  small  calculus,  as  I  have  shown  in  a  previous 
chapter,  may  lodge  at  the  orifice  of  the  diverticulum  of 
Vater,  and,  occluding  it,  may  convert  the  common  bile 
duct  and  the  duct  of  Wirsung  into  a  continuous  channel, 
thus  causing  the  penetration  of  bile  into  the  pancreas 


228  DISEASE  OF  THE  PANCREAS 

and  consequent  hemorrhagic  necrosis  of  the  pancreas. 
A  larger  calculus  present  in  the  diverticulum  of  Vater  or 
in  the  common  bile  duct,  slightly  above  its  junction  with 
the  pancreatic  duct,  may  temporarily  or  permanently 
compress  the  latter  and  produce  chronic  inflammatory 
changes  resembling  those  which  follow  ligation  of  the 
duct  in  animals. 

Doubtless  bacterial  infection  often  plays  a  part  in  the 
production  of  the  lesion,  and  in  two  additional  cases  of 
chronic  interlobular  pancreatitis  included  in  the  present 
series  the  bile  passages  containing  gall-stones  have  been 
the  seat  of  acute  suppurative  inflammation;  opportunity 
has  been  thus  afforded  for  ascending  infection  of  the  duct 


Fig.  33. — Biliary  calculus  (actual  .size)  wliich,  in  Case  XV.,  completely  filled  the  diver- 
ticulum of  Vater  and  occluded  the  duct  of  Wirsung;  chronic  interlobular  pancreatitis 
resulted.  Compare  with  the  small  calculus  which  in  Case  I  (see  Fig.  20)  caused  acute 
hemorrhagic  necrosis  of  the  pancreas. 

of  Wirsung.  In  neither  case  has  a  calculus  been  found 
compressing  the  pancreatic  duct,  but  such  compression 
may  have  occurred  at  some  previous  time  during  the  ex- 
pulsion of  a  stone.  Since,  however,  the  pancreatic  ducts 
are  the  seat  of  acute  inflammatory  changes  it  is  not  im- 
probable that  chronic  inflammation  may  have  been  the 
result  of  infection  originating  in  the  actively-inflamed 
bile  passages. 

Malignant  Growth. — In  five  of  my  cases  chronic  in' 
terstitial  pancreatitis  was  caused  by  a  malignant  growth 
compressing  or  invading  the  organ.  In  one  instance 
a  primary  carcinoma  of  the  pancreas  arising  in  the  head 
of  the  gland  compressed  the  duct  of  Wirsung  and  pro- 
duced chronic  interstitial  inflammation  with  formation 


CHRONIC  INTERSTITIAL  PANCREATITIS         229 

of  numerous  small  cysts  closely  crowded  together  in  the 
body  and  tail  of  the  pancreas. 

In  a  second  case,  previously  described  (Case  XII), 
advanced  chronic  interstitial  inflammation  followed  the 
development  of  a  carcinoma  of  the  bile  papilla  and  diver- 
ticulum of  Vater.  Infection  from  the  ulcerated  surface 
upon  which  the  duct  opened  was  with  great  probability 
an  important  factor  in  producing  the  advanced  chronic 
interstitial  inflammation  which  resulted. 

In  three  cases  chronic  inflammatory  changes  followed 
invasion  of  the  gland  by  a  carcinomatous  new  growth  of 
the  stomach.  When  the  head  of  the  gland  is  invaded 
there  is  a  diffuse  interstitial  change,  but  where,  as  in  two 
cases,  the  body  is  invaded  while  the  head  is  not  in  contact 
with  the  tumor,  inflammatory  alterations  occur  only  in 
that  part  of  the  gland  distal  to  the  point  at  which  the 
duct  is  compressed.  The  carcinomatous  tissue,  more- 
over, acts  as  a  local  inflammatory  irritant  and  in  its  im- 
mediate neighborhood  there  is  proliferation  of  the  stroma 
replacing  the  parenchymatous  elements. 

Ascending  Infection  from  the  Duodenum. — Under 
normal  conditions  the  pancreas,  like  other  glands  of  the 
gastro-intestinal  tract,  is  protected  against  the  entrance 
of  micro-organisms.  The  valve-like  folds  within  the 
diverticulum  of  Vater  prevent  the  regurgitation  of  ma- 
terial from  the  duodenum  into  the  duct,  and  if  after  death 
fluid  is  forced  under  considerable  pressure  into  the  duo- 
denum, tied  above  and  below  the  gland,  none  enters  the 
duct.  The  flow  of  secretion,  washing  away  foreign  ma- 
terial, doubtless  has  a  part  in  the  protection  of  the  gland. 

Korte  has  produced  chronic  inflammation  of  the  pan- 
creas by  injecting  Bacillus  coli  into  the  pancreatic  duct, 
and  has  obtained  a  similar  result  by  injecting  fecal  ma- 


230  DISEASE  OF  THE  PANCREAS 

terial.  By  an  ingenious  method  Carnot  has  produced 
conditions  by  which  an  ascending  infection  from  the 
duodenum  results.  A  thread,  inserted  into  the  pancre- 
atic duct,  and  through  its  orifice  into  the  duodenum,  has 
been  left  fixed  in  this  position.  Advanced  sclerosis  of 
the  gland  has  resulted,  and  the  walls  of  the  ducts  have 
been  thickened  and  infiltrated  with  leucocytes,  while  the 
interstitial  tissue  of  the  gland  has  been  much  increased. 
Association  of  Chronic  Interlobular  Pancreatitis  and 
Persistent  Vomiting. — In  four  of  the  thirty  cases  which 
I  have  observed,  advanced  chronic  interstitial  inflamma- 
tion has  been  found  in  individuals  who  during  life  have 
suffered  with  persistent  vomiting.  Since  this  disease  of 
the  pancreas  is  notably  one  of  advanced  life,  twenty-five 
of  thirty  cases  occurring  after  the  age  of  forty  years,  two 
of  these  cases  in  young  women  suggest  some  unusual 
etiological  factor.  In  a  third  case  chronic  pancreatitis 
has  followed  persistent  vomiting  in  a  man  forty-nine 
years  of  age,  who  though  once  addicted  to  alcohol  has  for 
ten  years  led  a  temperate  life ;  chronic  gastritis  has  been 
found  at  autopsy.  In  the  fourth  case  vomiting  has 
accompanied  carcinomatous  constriction  of  the  terminal 
part  of  the  duodenum.  In  all  of  these  cases  the  clinical 
history  affords  evidence  of  continued  gastric  or  gastro- 
intestinal disease — namely,  epigastric  pain,  nausea,  and 
vomiting.  Since  the  associated  conditions  apparently 
favor  infection  of  the  duct,  these  cases  have  been  de- 
scribed under  the  present  heading. 

Case  XVI. — The  patient,  a  deaf  mute,  female,  aged  thirty-one 
years,  entered  the  service  of  Dr,  Osier  complaining  of  "  heartburn " 
and  dyspepsia.     She  has  had  one  living  child  and  three  miscarriages, 


CHRONIC  INTERSTITIAL  PANCREATITIS         231 

and  is  at  present  pregnant.  Four  days  before  her  admission  she  began 
to  vomit;  the  vomiting  has  persistently  continued  and  has  recurred 
irrespective  of  the  taking  of  food.  In  the  afternoon  of  the  day  following 
admission  to  the  Hospital,  the  patient  becoming  much  weaker  and  semi- 
uneonscious,  vomiting  ceased.  Owing  to  the  severity  of  the  symptoms 
an  exploratory  laparotomy  was  performed.  There  was  no  return  of 
vomiting  untU  twelve  days  later,  when  it  recurred  with  its  previous 
persistence.  It  was  decided  to  empty  the  uterus,  and  an  ovum,  two  and 
a  half  months  old,  was  removed.  The  patient  died  on  the  twenty- 
second  day  after  her  admission.     Sugar  was  not  found  in  the  urine. 

Anatomical  Diagnosis. — ^Endometritis  of  the  puerperal  uterus. 
Anomalous  artery,  a  branch  of  the  aorta  penetrating  the  substance  of 
the  right  lung;  rupture,  with  formation  of  cavity  containing  blood- 
clots.     Chronic  interlobular  pancreatitis. 

The  stomach  is  normal,  save  for  the  presence  of  a  few  submucous 
ecchymoses;  the  duodenum  is  normal  in  appearance.  The  pancreas  is 
almost  board-like  in  consistence.  The  interlobular  tissue  is  dense  and 
fibrous,  containing  many  spindle-shaped,  lymphoid,  eosinophile,  and 
plasma  cells.  Entire  lobules  are  at  times  partially  destroyed,  a  few 
scattered  acini  remaining  in  the  proliferated  stroma,  but  in  general  the 
sharply  defined  lobules  are  not  invaded  by  the  process. 

Case  XVII, — ^H,  B,,  female,  aged  twenty-eight  years,  was  ad- 
mitted to  the  service  of  Dr.  Kelly  complaining  of  bleeding  from  the 
vagina.  Her  present  illness  began  ten  months  before  her  admission. 
An  operation,  the  nature  of  which  she  did  not  know,  was  performed 
five  months  later,  and  was  followed  by  much  nausea  and  vomiting.  Pre- 
vious to  her  admission  she  had  been  much  nauseated,  and  states  that 
even  a  small  quantity  of  water  might  cause  her  to  vomit.  She  had 
colicky  pains  in  the  epigastrium.  Vaginal  examination  demonstrated 
the  presence  of  an  inoperable  fungating  carcinoma  of  the  cervix.  The 
urine  contained  no  sugar. 

Anatomical  Diagnosis. — Carcinoma  of  the  utems,  with  metastases 
in  the  broad  ligaments,  pelvic  and  lumbar  lymphatic  glands,  liver, 
and  rectum ;  double  pyelonephrosis ;  chronic  interlobular  pancreatitis. 

There  are  no  noteworthy  changes  in  the  stomach,  intestine,  or  bile 
passages.  The  pancreas  is  firm  in  consistence  and  on  section  very 
compact  in  texture.     The  interlobular  tissue  is  much  thickened,  dense 


232  DISEASE  OF  THE  PANCREAS 

and  fibrous,  but  contains  lymphoid  and  plasma  cells  in  considerable 
number. 

Case  XVIII. — The  patient,  male,  aged  forty-nine  years,  was  ad- 
mitted to  the  service  of  Dr.  Osier  complaining  of  rheumatism,  cough, 
shortness  of  breath,  and  indigestion.  Ten  years  ago  he  had  used  alcohol 
in  excess,  but  for  the  last  ten  years  had  only  taken  an  occasional  drink. 
For  a  year  past  he  had  attacks  of  vomiting  without  any  apparent 
cause  and  with  no  relation  to  the  taking  of  food,  occurring  sometimes 
in  the  morning  before  breakfast.  He  died  on  the  fourth  day  after 
admission  with  symptoms  of  mitral  insufficiency.  The  urine  contained 
no  sugar. 

Anatomical  Diagnosis. — Chronic  endocarditis  of  the  mitral  valve; 
dilatation  and  hjrpertrophy  of  the  heart;  cardiac  thrombi;  chronic 
passive  congestion  of  the  viscera;  infarcts  of  the  lungs;  acute  and 
chronic  gastritis ;  ulceration  of  the  ileum  and  colon ;  chronic  interlobular 
pancreatitis  with  lipomatosis. 

The  mucosa  of  the  stomach,  covered  by  tenacious  mucus,  is  puffy, 
red  and  studded  with  small  submucous  ecehymoses.  The  pancreas 
weighs  152  Gm.  The  glandular  tissue  is  in  great  part  replaced  by  fat, 
separating  groups  of  lobules;  within  these  groups  individual  lobules 
are  separated  by  thickened  strands  of  dense  stroma  containing  many 
lymphoid  cells;  in  places  are  lobules  undergoing  disintegration. 

The  cases  just  described  illustrate  the  occurrence  of 
chronic  interlobular  pancreatitis  in  individuals  who  dur- 
ing life  have  suffered  with  persistent  vomiting.  They 
indicate  the  existence  of  some  relationship  between 
gastro-intestinal  disturbance  and  chronic  lesion  of  the 
pancreas.  It  is  improbable  that  persistent  vomiting  has 
been  caused  by  pancreatic  disease,  since  in  many  cases 
the  latter  has  existed  unaccompanied  by  this  symptom. 
Such  vomiting  has  doubtless  been  associated  with  con- 
ditions favoring  ascending  infection  of  the  pancreatic 
duct.  The  mechanical  effect  of  vomiting  upon  the  ducts 
and  their  contents  is  difficult  to  determine. 


CHRONIC  INTERSTITIAL  PANCREATITIS         233 

The  type  of  the  accompanying  pancreatic  lesion 
favors  the  probability  of  infection  by  way  of  the  duct, 
for  here  pancreatitis  is  typically  interlobular  and  resem- 
bles that  observed  in  those  cases  where  infection  of  the 
pancreas  has  followed  lesions  of  the  gall-ducts  with  or 
without  duct-obstruction.  This  explanat&on  receives 
further  confirmation  by  the  following  case,  in  which  per- 
sistent vomiting  has  been  the  result  of  partial  occlusion 
of  the  terminal  part  of  the  duodenum. 

Case  XIX. — Mrs.  F.  G.,  aged  fifty-one  years,  entered  the  sei-viee 
of  Dr.  Osier  seven  weeks  before  her  death,  complaining  of  nausea, 
vomiting,  and  loss  of  weight.  Her  uteiiis  had  been  removed  seven 
years  before  by  Dr.  Kelly  for  carcinoma  of  the  cervix;  she  had 
since  enjoyed  good  health.  Two  months  before  re-entering  the  hospital 
she  was  attacked  with  very  severe  vomiting,  occurring  often  five  or 
six  times  a  day  and  unaccompanied  by  nausea.  While  in  the  Hospital 
there  were  frequently  repeated  attacks  of  vomiting,  usually  at  intervals 
of  from  twelve  to  eighteen  hours.     No  sugar  was  found  in  the  urine. 

Anatomical  Diagnosis. — Recurrent  adenocarcinoma  of  the  retro- 
peritoneal Ijrmphatie  glands  and  of  the  peritoneum;  indurated  carcino- 
matous tissue  constricting  the  duodenum  and  left  ureter;  multiple 
abscesses  of  kidney;  cystitis;  bronchopneumonia;  fatty  degeneration 
of  the  liver;  fibrous  myocarditis. 

Sclerotic  adenocarcinoma  invading  the  wall  of  the  duodenum  at  its 
termination  has  contracted  the  lumen  to  a  diameter  of  12  mm.  The 
pancreas  is  very  firm,  and  upon  the  surface  individual  lobules  are 
sharply  defined.  Microscopic  examination  shows  interlobular  inflam- 
mation of  moderate  intensity,  the  lobulation  being  accentuated  by  thick- 
ened fibrous  bands  containing  lymphoid,  plasma,  and  eosinophile  cells 
in  fair  abundance. 

Alterations  of  the  Blood-Vessels;  Arterial  Sclerosis. 
— In  the  cases  already  considered  chronic  pancreatitis 
has  been  secondary  to  alterations  occurring  in  the  ducts ; 


234  DISEASE  OF  THE  PANCREAS 

in  another  group  of  cases  the  ducts  are  unchanged  and 
the  lesion  is  referable  to  the  blood-vessels  or  to  toxic  sub- 
stances brought  to  the  gland  by  the  blood.  In  the  pan- 
creas, as  in  other  organs,  general  arterial  sclerosis  has 
been  thought  to  be  the  cause  of  fibroid  induration,  and  G. 
Hoppe-Seyler  ^2  and  Fleiner  ^^  have  described  cases  of 
chronic  interstitial  pancreatitis,  attributed  by  them  to 
obliterating  endarteritis.  Both  writers  think  that  changes 
in  the  vessels  are  followed  by  nutritive  disturbances  which 
cause  degeneration  of  the  parenchyma  and  its  replace- 
ment by  fibrous  tissue.  The  condition,  Fleiner  suggests, 
is  analogous  to  the  contracted  kidney  which  is  at  times 
associated  with  general  arterial  sclerosis  and  to  changes 
in  the  liver,  heart,  and  brain  following  arterial  diseases. 
In  the  following  case  of  diabetes  advanced  arterial 
sclerosis  is  accompanied  by  chronic  interacinar  pancrea- 
titis. Here  both  gangrene  of  the  foot  and  pancreatic 
lesion  are  referable,  in  part  at  least,  to  arterial  sclerosis. 

Case  XX. — The  patient,  a  woman,  aged  sixty-three  years,  entered 
the  Johns  Hopkins  Hospital  suffering  with  gangrene  of  the  right  foot, 
which  had  begun  five  weeks  before.  Sugar  was  discovered  in  the  urine. 
Death  occurred  with  coma  twelve  days  after  admission.  The  virine  had 
contained  2.2  per  cent,  of  sugar;  preceding  death  acetone  was  abun- 
dant. 

Anatomical  Diagnosis. — General  arterial  sclerosis;  calcification  of 
the  coronary  arteries  and  of  the  right  posterior  tibial  and  dorsalis  pedis 
arteries.     Gangrene  of  the  right  foot.     Chronic  interacinar  pancreatitis., 

The  pancreas,  weighing  82  Gm.,  is  firm  in  consistence  and  is  sur- 
rounded and  infiltrated  by  abundant  fat.  The  splenic  artery  in  contact 
with  the  gland  is  tortuous  and  partially  calcified.     There  is  diffuse  in- 

'■"  hoc.  cit.,  p.  211. 

''Fleiner:  Beriiner  klin,  Woch.,  1894,  xxxi,  5,  38. 


CHRONIC  INTERSTITIAL  PANCREATITIS         235 

crease  of  the  interacinar  stroma  which  is  poor  in  cells.  The  islands 
of  Langerhans  are  often  surrounded  by  thickened,  capsule-like  strands 
of  fibrous  tissue,  and  similar  proliferation  of  connective  tissue  has 
occurred  along  the  course  of  their  capillary  vessels.  SmaU  arteries 
throughout  the  parenchyma  not  infrequently  show  obliterating  endar- 
teritis and  hyaline  changes  of  the  middle  coat. 

Studies  of  G.  Hoppe-Seyler  ^^  have  furnished  addi- 
tional evidence  that  pancreatitis  in  association  with  arte- 
rial sclerosis  is  interacinar  in  type.  The  frequent  asso- 
ciation of  diabetes  mellitus  with  interacinar  pancreatitis 
and  arterial  sclerosis  is  well  shown  by  the  statistics  of 
Cecil.2^  Among  ninety  cases  of  diabetes  interacinar  pan- 
creatitis occurred  in  sixty-seven  cases  (73  per  cent.)  and 
arterial  sclerosis  was  present  in  all  save  two  of  these 
cases;  the  arteries  of  the  pancreas  were  thickened  and 
hyaline,  and  in  one-fourth  of  the  cases  there  was  gan- 
grene of  the  extremities,  doubtless  referable  to  the  same 
arterial  disease.  Nevertheless,  general  arterial  scle- 
rosis, which  may  be  advanced  in  one  group  of  arteries 
and  absent  in  another,  may  be  unaccompanied  by  any 
change  in  the  pancreas. 

Venous  Congestion. — A  second  alteration  of  the  blood- 
vessels assigned  as  a  cause  of  chronic  pancreatitis  is 
chronic  passive  congestion.  Friedreich  states  that  the 
lesion  is  not  infrequently  the  result  of  long-continued 
venous  gorging,  occurring  in  chronic  diseases  of  the 
heart,  lungs,  and  liver.  The  changes,  he  says,  are  usually 
slight  and  do  not  cause  destruction  of  the  glandular 
elements.  The  frequency  of  chronic  congestion  of  the 
abdominal    viscera,    and    the    relative    infrequency    of 

**  Hoppe-Seyler :  Deutsches  Arch,  f .  klin.  Med.,  1904,  Ixxxi,  119. 
■"  Log.  cit. 


236  DISEASE  OF  THE  PANCREAS 

chronic  interstitial  inflammation  of  the  pancreas,  is  evi- 
dence that  the  former  condition  is  not  commonly  a  cause 
of  the  latter.  Chronic  passive  congestion  may  doubtless 
produce  slight  proliferation  of  the  interstitial  tissue,  but 
is  an  unimportant  factor  in  the  production  of  chronic 
pancreatitis. 

The  following  case  serves  to  illustrate  how  small  is 
the  influence  of  advanced  chronic  passive  congestion  in 
causing  inflammatory  changes  in  the  gland,  for  the  slight 
increase  of  interstitial  tissue  which  is  present  is  probably 
due  to  local  changes  in  the  wall  of  veins  plugged  by  car- 
cinomatous tissue  and  to  accumulation  of  pigment  both 
in  the  secreting  cells  and  in  the  interstitial  tissue  of  the 
organ. 

Case  XXI. — Anatomical  Diagnosis. — Primary  carcinoma  of  the 
liver  invading  and  occluding  the  portal  vein;  chronic  passive  conges- 
tion of  the  spleen,  pancreas,  stomach,  and  intestines;  ascites.  Chronic 
interstitial  pancreatitis  with  pigmentation. 

The  pancreas,  comprassed  by  the  distended  splenic  vein,  is  firm 
and  compact  in  texture  and  of  a  miiform  brownish-red  color. 
The  veins  are  widely  dilated,  and  are  occasionally  plugged  by  car- 
cinomatous tissue.  There  is  a  very  slight  increase  of  the  interlobular 
tissue,  which  is  denser  than  usual,  and  among  the  acini  occur*  irregular 
patches  of  interstitial  tissue,  poor  in  cells.  Small  hemorrhages  have  in 
places  occurred  into  the  interlobular  tissue,  and  both  hei'e  and  within 
the  secreting  cells  is  found  brown  iron-containing  pigment. 

Chronic  pancreatitis,  like  corresponding  changes  in 
the  liver  and  kidney — namely,  cirrhosis  of  the  liver  and 
chronic  interstitial  nephritis — is  caused  by  the  action  of 
toxic  substances  present  in  the  blood.  Various  condi- 
tions presumably  capable  of  producing  such  substances 
have  been  assigned  as  causes  of  chronic  pancreatitis; 


CHRONIC  INTERSTITIAL  PANCREATITIS         237 

those  notably  worthy  of  consideration  are  tuberculosis, 
syphilis,  and  alcohol,  named  in  the  probable  order  of  their 
increasing  importance. 

Tuberculosis. — Carnot,  citing  observations  of  Ancelet 
and  other  writers,  has  claimed  that  chronic  pancreatitis 
is  not  uncommon  with  tuberculosis.  He  examined  the 
pancreas  in  patients  dying  with  tuberculosis,  and  while 
in  the  majority  no  lesion  was  demonstrable,  in  seven  cases 
he  found  a  variable,  usually  moderate  increase  of  the 
connective  tissue  normally  present  about  the  vessels  and 
ducts  and  between  the  lobules.  Finding  tubercles  in  only 
one  case  he  thinks  that  the  specific  lesion  of  tuberculosis 
is  uncommon  in  the  pancreas.  Carnot  was  able  to  pro- 
duce chronic  inflammatory  changes  in  the  pancreas  of 
dogs,  somewhat  varied  in  extent  and  character,  by  in- 
jecting suspensions  of  Bacillus  tuberculosis  into  the 
duct  or  into  the  parenchyma  of  the  organ,  but  the  lesion 
presented  none  of  the  specific  characters  of  tuberculosis, 
and  tubercle  bacilli  were  not  demonstrable  in  the  tissues. 

Two  of  the  thirty  instances  of  chronic  pancreatitis 
previously  cited  occurred  in  individuals  who  suffered  with 
advanced  tuberculous  lesions  and  in  one  of  these  in- 
stances miliary  tubercules  were  found  in  the  pancreas. 
In  three  additional  autopsies  performed  in  the  patho- 
logical laboratory  of  the  Johns  Hopkins  Hospital  tuber- 
culous lesions  were  present  in  the  pancreas,  but  there 
was  no  generalized  proliferation  of  the  interstitial  tissue. 

Since  tuberculosis,  it  is  well  known,  is  a  frequent 
complication  of  diabetes,  its  relationship  to  alterations 
of  the  pancreas  are  of  much  interest.  In  the  cases  just 
cited  diabetes  has  not  been  present  and  the  lesion  of 
moderate  severity  is  interlobular,  a  type  of  inflammation 


238  DISEASE  OF  THE  PANCREAS 

accompanied  by  diabetes  only  when  very  far  advanced. 
There  is,  it  appears,  no  reason  to  suppose  that  diabetes 
may  be  caused  by  pancreatitis  resulting  from  tuber- 
culosis. 

Syphilis. — The  autopsy  records  of  the  pathological 
laboratory  of  the  Johns  Hopkins  Hospital  furnish  no 
instance  in  which  chronic  pancreatitis  has  been  associ- 
ated with  visceral  syphilis;  and  though  the  literature 
demonstrates  that  the  two  conditions  occur  in  conjunc- 
tion, acquired  syphilis  is  certainly  not  the  most  common 
cause  of  the  lesion,  as  Hansemann,^^  Kasahara,^^  and 
other  writers  believe.  In  only  one  of  my  thirty  cases 
was  a  history  of  syphilis  obtained;  and  in  this  case 
chronic  pancreatitis  with  formation  of  cysts  was  caused 
by  primary  carcinoma  of  the  pancreas  compressing  the 
duct. 

AlcoJiol. — The  common  cause  of  cirrhosis  of  the  liver 
is  excessive  use  of  alcoholic  drinks.  Cirrhosis  is  rela- 
tively infrequent  when  compared  with  the  prevalence  of 
alcoholic  indulgence;  but  here,  as  with  many  diseases, 
other  conditions  are  necessary  in  order  that  the  lesion 
may  result.  Alcoholic  excess  is  likewise  regarded  as 
a  frequent  cause  of  chronic  interstitial  pancreatitis,  and 
in  many  instances  a  history  of  alcoholic  indulgence  can 
be  obtained.  Friedreich  found  at  autopsy  upon  a  drunk- 
ard chronic  pancreatitis,  cirrhosis  of  the  liver,  and  granu- 
lar kidneys.  Chvostek,-^  Dieckhoff,  and  Oser  have 
described  cases  in  which  cirrhosis  of  the  liver  and  chronic 
pancreatitis  were  associated  in  alcoholics.    In  eight  of 


"  Hansemann :  Zeit.  f.  klin.  Med.,  1S94,  xxvi,  191. 
""  Kasahara :  "Virchow's  Arch.,  1S96,  cxliii,  111. 
"*  Chvostek :  Wiener  med.  Blatter,  1879,  ii,  791. 


CHRONIC  INTERSTITIAL  PANCREATITIS         239 

the  present  thirty  cases  a  history  of  alcoholic  excess  has 
been  obtained,  but  in  three  of  these  cases  chronic  inflam- 
mation of  the  organ  has  followed  obstruction  of  its  duct 
by  biliary  or  pancreatic  calculi,  and  is  indirectly,  if  at 
all,  referable  to  the  use  of  alcohol. 

In  the  following  case  chronic  interlobular  pancreatitis 
unaccompanied  by  cirrhosis  of  the  liver  has  been  found  at 
autopsy  in  an  individual  dying  with  delirium  tremens. 

Case  XXII. — J.  M.,  male,  aged  fifty-three  years,  was  admitted  to 
the  service  of  Dr.  Osier  with  delirium.  His  wife,  from  whom  a  satis- 
factory history  was  not  obtained,  stated  that  he  had  been  drinking 
very  heavily  for  a  month,  and  on  the  morning  before  his  admission 
became  delirious  and  feverish.  The  patient  was  completely  unconscious, 
the  temperature  rose  to  105.4°  F.,  and  he  died  on  the  second  day 
after  admission. 

Anatomical  Diagnosis. — Bronchitis  and  beginning  aspiration  pneu- 
monia; acute  diphtheritic  and  hemorrhagic  colitis;  fatty  degeneration 
of  the  liver;  chronic  interlobular  pancreatitis;  fat  necrosis. 

The  pancreas,  of  normal  size,  is  very  firm  in  consistence,  and  the 
interstitial  tissue  appears  to  be  indurated.  The  duets  are  normal. 
Numerous  small  foci  of  fat  necrosis  occur  about  the  pancreas  and  in 
the  transverse  mesocolon.  Microscopic  examination  shows  typical 
chronic  interlobular  pancreatitis,  and  the  interstitial  tissue  contains 
numerous  lymphoid  cells. 

Few  reported  instances  of  chronic  pancreatitis  not 
dependent  upon  lesions  of  the  duct  are  described  with 
sufficient  detail  to  determine  if  there  has  been  alcoholic 
indulgence,  and  a  review  of  them  would  afford  statistics 
of  little  value.  Alcohol  being  the  common  cause  of  cir- 
rhosis of  the  liver,  the  association  of  chronic  pancreatitis 
with  this  lesion  is  significant. 

Association  of  Chronic  Pancreatitis  luith  Cirrhosis  of 


240  DISEASE  OF  THE  PANCREAS 

the  Liver. — Among  my  thirty  cases  of  chronic  pancrea- 
titis cirrhosis  of  the  liver  occurs  in  eight.  In  three  of 
these  cases  pancreatitis  is  indirectly,  if  at  all,  related  to 
the  lesion  of  the  liver  and  has  followed  readily  demon- 
strable changes  in  the  duct  of  Wirsung. 

Chronic  inflammation  of  the  liver  and  pancreas  have 
been  found  associated  by  Friedreich,  Chvostek,  Hanse- 
mann,  Dieckhoff,  Kasahara,  Oser,  and  Lefas.  In  six 
cases  of  chronic  interstitial  hepatitis  Kasahara  found  a 
marked  increase  of  connective  tissue  in  the  pancreas,  in 
two  a  slight  increase,  and  in  two  none  at  aU. 

Of  considerable  interest  are  the  observations  of 
Lefas  ;^^  with  the  so-called  atrophic  or  Laennec's  cir- 
rhosis he  finds  that  the  weight  of  the  pancreas  is  in- 
creased and  the  newly-formed  tissue,  which  is  poor  in 
cells,  is  uniformly  intralobular,  penetrating  the  paren- 
chyma and  isolating  groups  of  acini.  With  so-called 
hypertrophic  biliary  cirrhosis  of  Hanot  there  is  no 
increase  in  the  volume  of  the  pancreas,  but  the  inter- 
lobular tissue  is  increased  in  amount  and  in  density. 
Cases  which  I  have  observed  confirm  in  part  the  observa- 
tions of  Lefas. 

In  two  cases  previously  described  (Cases  XIII  and 
XIV)  chronic  interacinar  pancreatitis  accompanied  by 
diabetes  was  associated  with  cirrhosis  of  the  liver  of  the 
so-called  atrophic  type  of  Laennec.  In  only  one  was 
there  a  history  of  excessive  alcoholic  indulgence. 

An  excellent  illustration  of  the  dependence  of  chronic 
lesions  of  the  liver  and  of  the  pancreas  upon  the  same 
etiological  factor  is  furnished  by  the  disease  of  pig- 

=•  Lefas:  Arch.  gen.  de  med.,  1900,  n.  s.  iii,  539. 


CHRONIC  INTERSTITIAL  PANCREATITIS         241 

nient  metabolism,  first  described  by  Von  Recklinghausen, 
namely,  haemochromatosis. 

In  a  case  of  haemochromatosis  (see  page  368)  included 
in  the  present  series  cirrhosis  of  the  liver  was  accom- 
panied by  chronic  interacinar  pancreatitis. 

In  the  following  case  hypertrophic  cirrhosis  of  the 
type  of  Hanot  is  accompanied  by  interlobular  pancrea- 
titis, as  in  the  cases  described  by  Lefas ;  it  is  noteworthy 
that  the  condition  is  complicated  by  gall-stones,  which 
may  explain  the  occurrence  of  interlobular  pancreatitis. 

Case  XXIII. — The  patient,  male,  aged  fifty-six  years,  admitted 
to  the  service  of  Dr.  Osier  in  the  Johns  Hopkins  Hospital,  gave  a  his- 
tory of  having  used  whisky  in  excess.  For  the  last  year,  until  a  short 
time  ago,  he  has  had  attacks  of  vomiting,  and  during  the  last  six 
months  has  become  weak  and  short  of  breath.  The  liver  is  enlarged, 
and  there  are  ascites  and  other  evidences  of  portal  congestion.  Sugar 
has  not  been  found  in  the  urine. 

Anatomical  Diagnosis. — Hypertrophic  cirrhosis  (of  Hanot) ; 
ascites;  chronic  passive  congestion  of  spleen;  chronic  interlobular  pan- 
creatitis ;  cholelithiasis. 

The  liver,  weighing  2880  Gm.,  exhibits  the  gross  microscopic 
appearance  of  hypertrophic  ciiThosis  of  Hanot.  The  gall-bladder  con- 
tains many  small  facetted  calculi.  The  panerteas,  weigliing  60  Gm., 
is  very  firm  in  consistence  and  evidently  sclerotic.  The  duct  of  Wirsung 
in  the  body  and  tail  of  the  gland  is  dilated,  and  contains  solid  wax-like 
material.  Microscopic  examination  shows  that  the  lobules,  particu- 
larly in  the  body  and  tail,  are  separated  by  dense  sclerotic  tissue  showing 
little  tendency  to  penetrate  between  the  acini. 

In  a  second  case  included  in  my  series  previously  . 
cited  interlobular  pancreatitis  of  moderate  grade  accom- 
panied beginning  cirrhosis  in  a  woman  twenty-two  years 
of  age,  and  though  the  hepatic  lesion  corresponded  to 

16 


242  DISEASE  OF  THE  PANCREAS 

the  so-called  atrophic  or  Laennec's  cirrhosis,  the  altera- 
tion of  the  pancreas  differed  from  that  observed  in  such 
cases  by  Lefas  and  found  with  atrophic  cirrhosis  in 
Cases  XIII  and  XIV.  It  is  noteworthy,  however,  that 
the  lesion  was  associated  with  tuberculous  peritonitis, 
while  a  variety  of  chronic  lesions  co-existed  in  other 
organs. 

The  foregoing  data  concerning  the  etiology  of  chronic 
pancreatitis  may  be  summarized  in  the  following  con- 
clusions; 

(a)  Occlusion  of  the  pancreatic  ducts  by  gall-stones, 
pancreatic  calculi  or  other  obstruction  to  outflow  of  pan- 
creatic juice,  is  followed  by  interlobular  pancreatitis. 
Acute  inflammation  of  the  pancreatic  ducts  ascending 
from  the  duodenum  or  bile  duct  may  be  followed  by 
chronic  interlobular  pancreatitis. 

(h)  Arterial  sclerosis  is  a  frequent  cause  of  inter- 
acinar  pancreatitis.  Those  conditions  which  cause  cir- 
rhosis of  the  liver — for  example,  use  of  alcohol — not  in- 
frequently cause  chronic  interstitial  pancreatitis  which  in 
association  with  atrophic  cirrhosis  of  the  type  of  Laennec 
is  usually  interacinar. 

The  importance  of  these  conclusions  will  be  evident 
when  the  relation  of  diabetes  mellitus  to  chronic  pan- 
creatitis is  considered.  It  will  be  shown  that  interlobular 
pancreatitis  which  spares  the  islands  of  Langerhans,, 
and  only  when  far  advanced  injures  them,  is  rarely 
.  accompanied  by  diabetes,  whereas  interacinar  pancrea- 
titis which  attacks  these  structures  is  almost  constantly 
accompanied  by  diabetes  mellitus. 


CHRONIC  INTERSTITIAL  PANCREATITIS         243 

SYMPTOMS. 

Chronic  pancreatitis  is  rarely  accompanied  by  sucli 
definite  symptoms  that  its  recognition  is  possible  during 
life.  In  most  instances  a  considerable  part  of  the  paren- 
chyma is  nndestroyed,  and  is  capable  of  performing,  in 
part  at  least,  the  functions  of  the  gland.  Hence  chronic 
pancreatitis  may  be  unaccompanied  by  glycosuria  or  by 
any  disturbance  of  digestion.  Since  chronic  pancreatitis 
in  most  instances  follows  grave  disturbances  of  the 
stomach,  duodenum  or  bile  passages,  symptoms  of  the 
primary  disorder  are  predominant  and  hinder  recog- 
nition of  the  pancreatic  lesion.  On  the  other  hand,  dis- 
ease of  neighboring  organs  recognizable  by  clinical 
methods  may  suggest  the  presence  of  chronic  pan- 
creatitis. 

Symptoms  such  as  pain  in  the  epigastric  region,  per- 
hap&;  in  the  midscapular  region,  jaundice,  loss  of  weight 
and  weakness  have  been  frequently  found  in  association 
with  chronic  pancreatitis  but  cannot  be  referred  with  cer- 
tainty to  this  disease  since  they  may  be  caused  by  accom- 
panying changes  in  the  gastro-intestinal  tract  or  in  the 
biliary  passages.  Vomiting,  which  frequently  occurs 
with  chronic  pancreatitis,  may  be  referable  to  lesions  of 
adjacent  organs  and  there  is  evidence  indeed  that  it  may 
l}e  a  cause  of  pancreatitis.  Mayo  Eobson  and  Cammidge, 
who  alone  claim  that  chronic  pancreatitis  can  be  recog- 
nized with  considerable  frequency  during  life,  attach 
special  significance  for  diagnosis  to  progressive  wasting 
jaundice,  disturbances  of  gastric  digestion,  the  almost 
invariable  presence  of  the  reaction  of  Cammidge  in  the 
urine,  and  an  excess  of  unabsorbed  fecal  fat- of  which  the 


244  DISEASE  OF  THE  PANCREAS 

greater  part  has  not  been  split  to  form  fatty  acids  and 
soaps.     (See  Chapter  IV.) 

Enlargement  of  the  pancreas  caused  by  chronic  in- 
flammation is  not  recognizable  through  the  abdominal 
wall.  Under  normal  conditions  the  pancreas  is  not  pal- 
pable, but  in  individuals  with  thin  abdominal  walls,  ac- 
cording to  Osler,"^  particularly  in  women  with  enterop- 
tosis,  the  organ  can  be  felt. 

It  has  been  claimed  that  acute  or  chronic  inflammation 
with  swelling  of  the  head  of  the  pancreas  may  cause  jaun- 
dice by  compression  of  the  common  bile  duct;  chronic 
inflammation  with  sclerosis  and  contraction  of  newly- 
formed  tissue  surrounding  the  duct  as  it  passes  through 
the  gland,  it  is  believed,  may  constrict  and  occlude  the 
bile  duct.  Pourtoy^^  has  described  a  case  in  which  a 
sharply  localized  focus  of  sclerosis  of  obscure  origin  had 
caused  constriction  of  the  common  bile  duct,  with  jaun- 
dice. In  none  of  the  other  cases  collected  by  this  writer 
has  dissection  confirmed  his  claim  that  jaundice  may  be 
caused  by  diffuse  chronic  inflammation  of  the  pancreas. 
Jaundice  with  acute  or  chronic  inflammation  of  the  pan- 
creas is  in  most  instances  adequately  explained  by  chole 
lithiasis  or  other  hepatic  disease  preceding  or  accompany- 
ing the  pancreatic  lesion.  Disturbances  of  digestion 
such  as  fatty  stools  are  uncommon.  In  sixty-three  of 
ninety  cases  of  diabetes  Cecil  found  interacinar  pancrea- 
titis. Although  no  group  of  symptoms,  as  Lancereaux  ^^ 
has  claimed,  is  characteristic  of  diabetes  caused  by  pan- 

*°  Osier:  The  Diagnosis  of  Abdominal  Tumors,     New  York,  1894, 
p.  118. 

""Pourtoy:  Thesis,  Lyon,  1903. 

"Lancereaux:    Bull.  Acad,  de  med.,  1877,  2  s.,  vi,  1215. 


CHRONIC  INTERSTITIAL  PANCREATITIS         245 

creatic  lesion,  conditions  associated  with  the  disease  may 
give  evidence  that  it  accompanies  interacinar  inflamma- 
tion of  the  gland;  such  lesions  are  arterial  sclerosis  and 
cirrhosis  of  the  liver. 

In  a  considerable  number  of  cases  cited  in  the  litera- 
ture of  the  subject  arterial  sclerosis  has  been  associated 
with  chronic  interstitial  inflammation  of  the  pancreas. 
Where  advanced  arterial  sclerosis  accompanies  diabetes 
mellitus,  the  latter  disease  is  with  much  probability  refer- 
able to  interacinar  inflammation  of  the  pancreas. 

The  association  of  diabetes  mellitus  and  cirrhosis  of 
the  liver  has  been  very  frequently  observed,  and  in  some 
of  these  cases  the  pancreas  examined  at  autopsy  has 
been  found  to  be  the  seat  of  chronic  inflammatory 
changes.  Chronic  inflammation  of  the  pancreas  and  of 
the  liver  is  doubtless  in  such  cases  dependent  upon  the 
same  etiological  factors.  In  Cases  XIII  and  XIV  dia- 
betes and  atrophic  cirrhosis  have  coexisted  while  at 
autopsy  chronic  pancreatitis  of  the  interacinar  type  has 
been  demonstrable.  Seven  similar  cases  are  recorded  by 
Cecil.  Diabetes  with  cirrhosis  of  the  liver  is  with  much 
probability  indicative  of  interacinar  pancreatitis. 

One  form  of  chronic  interacinar  pancreatitis  with 
diabetes  and  cirrhosis  may  be  readily  recognized  during 
life.  Diabetes  with  haemochromatosis,  the  so-called 
bronzed  diabetes,  is  doubtless  in  all  cases  the  result  of 
chronic  interacinar  inflammation  affecting  the  pancreas 
and  implicating  the  islands  of  Langerhans.  The  com- 
bination of  symptoms  in  such  cases  is  characteristic. 
Diabetes  mellitus  is  associated  with  hypertrophic  cir- 
rhosis of  the  liver,  and  there  is  often  intense  pigmenta- 
tion of  the  skin.    In  a  case  described  by  Anschiitz,  fatty 


246  DISEASE  OF  THE  PANCREAS 

stools  gave  evidence  that  the  secretion  of  tlie  pancreas 
was  diminished  in  amount. 

Pancreatitis  as  a  Cornplication  of  other  Diseases. — It 
lias  been  repeatedly  stated  that  in  most  instances  both 
acute  and  chronic  inflammation  of  the  pancreas  are 
secondary  to  disease  of  other  organs.  Acute  or  chronic 
inflammation  may  be  the  result  of  an  ascending  infection 
of  the  pancreatic  ducts  having  its  origin  in  the  inflamed 
stomach,  duodenum,  or  bile  passages.  The  occurrence  of 
chronic  inflammation  in  association  with  persistent  vomit- 
ing has  been  emphasized. 

The  close  relationship  between  disease  of  the  liver  and 
of  the  pancreas  is  especially  noteworthy,  chronic  inflam- 
mation of  the  liver  and  pancreas,  doubtless  due  to  the 
same  etiological  factor,  not  infrequently  occurring  in 
conjunction.  Much  more  common,  however,  is  the  asso- 
ciation of  cholelithiasis  and  chronic  pancreatitis.  A  large 
gall-stone  lodged  in  the  terminal  part  of  the  common  bile 
duct,  or  indeed  within  the  diverticulum  of  Vater,  prevents 
the  escape  of  pancreatic  secretion,  unless  the  duct  of 
Santorini  affords  a  free  outlet,  and  chronic  interlobular 
inflammation  of  the  gland  results.  The  indurated  gland 
felt  during  an  operation  undertaken  for  the  removal  of 
gall-stones  in  the  common  duct  has  been  frequently  mis- 
taken for  malignant  growth.  Ability  to  distinguish  be- 
tween cancer  and  chronic  pancreatitis  will  have  an  im- 
portant influence  upon  the  prognosis  in  such  cases,  and 
removal  of  the  occluding  calculus  will  prevent  further 
development  of  the  pancreatic  lesion. 

From  a  clinical  stand-point  it  is  desirable  to  distin- 
guish between  an  interlobular  and  an  interacinar  type  of 
chronic  interstitial  pancreatitis. 


CHRONIC  INTERSTITIAL  PANCREATITIS        247 

Chronic  pancreatitis  of  the  interlobular  type  in  most 
instances  follows  obstruction  of  the  duct  by  pancreatic 
calculi,  by  biliary  calculi,  or  by  tumors  and  cysts  com- 
pressing the  duct  as  it  passes  through  the  head  of  the 
gland.  In  some  of  such  cases  disturbances  of  digestion, 
namely,  steatorrhoea  or  azotorrhcea,  consequent  upon  loss 
of  the  pancreatic  secretion,  have  been  noted.  Acute  and 
chronic  inflammation  of  the  stomach  and  duodenum  on 
the  one  hand,  and  of  the  bile  passages  on  the  other,  may, 
as  in  cases  previously  described,  be  accompanied  by  inter- 
lobular pancreatitis,  the  result  of  ascending  infection.  I 
have  described  four  cases  in  which  chronic  interlobular 
inflammation  was  found  at  autopsy  in  individuals  who 
had  suifered  with  persistent  vomiting,  caused  doubtless 
in  three  cases,  presumably  in  all,  by  lesions  of  the  stom- 
ach or  of  the  duodenum. 

Interlobular  pancreatitis  is  accompanied  by  diabetes 
only  when  the  lesion  is  so  far  advanced  that  dense  scle- 
rotic tissue,  which  replaces  the  secreting  parenchyma, 
surrounds  and  compresses  the  islands  of  Langerhans. 
Glycosuria  was  noted  in  only  one  of  my  twenty-two  cases 
of  interlobular  pancreatitis  and  interlobular  pancreatitis 
was  present  in  only  four  of  ninety  cases  of  diabetes  stud- 
ied by  Cecil.  In  my  case  chronic  interlobular  pancrea- 
titis was  caused  by  calculi  obstructing  the  pancreatic 
ducts ;  glycosuria  was  of  mild  type,  and  disappeared  when 
the  patient  was  given  a  diet  poor  in  carbohydrates. 

In  at  least  five  of  fifteen  cases  in  which  Wille  found 
alimentary  glycosuria,  chronic  inflammation — from  his 
description  presumably  of  the  interlobular  type — was 
found  at  autopsy.  Where  chronic  pancreatitis  is  sus- 
pected, the  presence  of  alimentary  glycosuria,  tested  by 


248  DISEASE  OF  THE  PANCREAS 

the  administration  of  sugar,  would  give  additional 
evidence. 

Mayo  Eobson  and  Cammidge  believe  that  chronic  pan- 
creatitis is  a  dangerous  complication  of  cholelithiasis 
and  may  cause  death  with  increasing  weakness  and 
emaciation.  Removal  of  gall-stones  and  drainage  of  the 
gall-bladder  (they  recommend  cholecystenterostomy) 
check  these  symptoms,  they  believe,  and  they  have  re- 
peatedly observed  recovery  following  the  operation 
although  induration  of  the  head  of  the  pancreas  at  the 
time  of  operation  has  indicated  the  presence  of  chronic 
pancreatitis.  It  is  difficult  to  determine  how  much  the 
pancreatic  lesion  increases  the  severity  of  symptoms 
caused  by  cholelithiasis.  Mayo  ^^  has  not  found  that  the 
pancreatic  lesion  has  greatly  influenced  the  prognosis 
of  operations  performed  for  the  removal  of  gall-stones. 

Chronic  interlobular  pancreatitis  caused  by  gall- 
stones rarely  if  ever  causes  such  advanced  destruction 
of  the  pancreas  that  diabetes  mellitus  ensues.  When 
chronic  interlobular  pancreatitis  follows  occlusion  of  the 
pancreatic  duct  caused  by  carcinoma,  by  cyst  or  by  pan- 
creatic calculi,  diabetes  mellitus  results  only  when  the 
pancreatic  parenchyma  is  in  great  part  replaced  by 
fibrous  tissue,  and  islands  of  Langerhans  which  tend  to 
remain  uninjured  are  finally  attacked.  Glycosuria  indi- 
cates that  the  lesion  is  far  advanced  and  suggests  grave 
prognosis. 

Distinctive  of  the  interacinar  form  of  chronic  pan- 
creatitis are  glycosuria  and  other  s^nuptoms  of  diabetes 
mellitus. 

""Loc.  cit.,  p.  226. 


CHAPTER  X. 

TUBERCULOSIS    OF    THE    PANCEEAS SYPHILIS. 

ViECHOw  1  has  cited  the  pancreas  to  illustrate  local 
immunity  from  tuberculosis.  Whereas  large  tuberculous 
lesions  are  rare  and  functional  disturbance  referable  to 
tuberculosis  almost  unknown,  the  occurrence  of  miliary 
tubercles  in  association  with  tuberculosis  of  other  organs 
is  not  uncommon.  Kudrewetzky^  found  miliary  tuber- 
cles of  the  pancreas  in  12  of  128  bodies  with  tuberculosis 
in  other  organs ;  almost  half  of  these  secondary  tubercu- 
lous lesions  of  the  pancreas  occurred  in  children.  Among 
18  cases  of  acute  miliary  tuberculosis  in  6  the  pancreas 
contained  tubercles.  Tubercles  were  usually  situated 
within  the  lobules,  less  frequently  in  the  interlobular 
tissue  and  rapidly  underwent  caseation.  With  chronic 
tuberculosis  large  tubercles  replacing  groups  of  acini 
with  newly-formed  tissue,  were  found  occasionally. 

Tuberculosis  may  occur  in  the  pancreas  by  extension 
from  neighboring  organs.  The  disease  may  begin  in 
lymphatic  glands  which  are  in  contact  with  and  even 
within  the  substance  of  the  gland.  Sendler  ^  found  a 
small  tumor  above  the  umbilicus  of  a  woman  who  had 
suffered  with  pain  and  vomiting,  and  a  small  mass  which 
proved  to  be  a  tuberculous  lymphatic  gland  was  removed 
by  operation  from  the  head  of  the  pancreas.     Carnot^ 

^  Virehow :  Die  krankhaf  ten  Gesehwiilste,  Berlin,  1864-65,  ii,  677. 
'  Kudrewetzky :  Zeit.  f ,  Heilk.,  1892,  xiii,  101. 
'  Sendler :  Miineliener   med.    Woeb.,   1896,    xliii,    1193 ;    Deutsche 
Zeit.  f .  Chir.,  1896,  xliv,  329. 
*  Loc.  cit. 

249 


250  DISEASE  OF  THE  PANCREAS 

found  tuberculosis  of  the  splenic  end  of  the  pancreas  in 
contact  with  a  tuberculous  kidney. 

It  is  noteworthy  that  fat  necrosis  in  contact  with  the 
pancreas  has  been  mistaken  for  tuberculosis. 

Primary  tuberculosis  of  the  pancreas  has  been  de- 
scribed. Aran  ^  found  a  tuberculous  mass  the  size  of  a 
hen's  egg  in  the  tail  of  the  pancreas  of  a  woman  aged 
twenty-five  years,  who  had  suffered  with  pain  in  the 
epigastrium,  vomiting  and  discoloration  of  the  skin ;  there 
were  miliary  tubercles  about  the  mass  and  in  the  spleen. 
Mayo  ^  has  described  pancreatic  tuberculosis  in  a  woman 
thirty-eight  years  old,  who  had  suffered  with  pain  in  the 
right  hypogastrium  during  sixteen  weeks;  there  was 
jaundice  several  weeks  before  death,  and  a  tumor  was 
palpable  just  above  the  umbilicus.  The  head  of  the  pan- 
creas was  much  enlarged  by  a  tuberculous  mass  which 
had  compressed  the  common  bile  duct  and  caused  con- 
siderable distention  of  the  gall-bladder.  Tubercles  re- 
garded as  secondary  were  found  in  lymphatic  glands, 
thymus,  and  kidneys.  In  a  case  described  by  Chvostek  ^ 
the  pancreas  contained  caseous  masses  the  size  of  a  wal- 
nut; the  enlarged  and  sclerotic  organ  compressed  both 
common  bile  duct  and  duodenum. 

SYPHILIS. 

Congenital  Syphilitic  Pancreatitis. — Birch-Hirschf  eld'^ 
first  drew  attention  to  the  frequency  with  which  the 
pancreas  is  affected  by  congenital  syphilis.  He  found 
the  pancreas  affected  in  thirteen  of  twenty-three  cases  of 


°  Cited  by  Senn :  Outlines  of  Human  Pathology. 
"Chvostek:    Wiener  med.  Blatter,  1879,  ii,  791. 
'  Birch-Hirschf  eld :    Gerhardt's   Handbuch    d.    Kinderkrankheiten, 
iv,  Abt.,  ii,  753,  Tiibingen,  1880. 


TUBERCULOSIS— SYPHILIS  251 

congenital  lues,  but  studying  a  second  group  of  cases, 
found  changes  in  the  organ  only  twenty-nine  times  in  one 
hundred  and  twenty-four  syphilitic  new-born.  In  six  in- 
stances Schlesinger  ^  found  the  enlarged  firm  organ  the 
seat  of  a  diffused  interstitial  pancreatitis  characterized 
by  proliferation  of  interlobular  and  interacinar  tissue 
penetrating  in  places  between  the  cells  of  the  acini.  This 
inflammatory  new  growth,  he  thinks,  is  followed  by  de- 
struction of  the  parenchymatous  elements,  which,  though 
they  do  not  exhibit  appearances  of  degeneration,  atrophy 
and  disappear.  New  growth  of  interstitial  tissue,  he 
finds,  has  its  origin  about  the  blood-vessels ;  the  arteries 
are  the  seat  of  a  syphilitic  peri-arteritis.  As  the  lesion 
progresses  the  capillary  network  about  the  acini  disap- 
pears. Schlesinger  has  observed  that  the  islands  of 
Langerhans  are  neither  invaded  by  the  new  growth  of 
interstitial  tissue  nor  implicated  in  the  atrophy  which 
affects  the  cells  of  the  acini. 

Two  instances  of  congenital  syphilis  of  the  pancreas 
are  here  recorded ;  the  relation  of  the  islands  of  Langer- 
hans to  the  inflammatory  process  has  considerable 
interest. 

Case  XXIV. — An  infant,  40  cm.  in  length,  lived  three  hours. 

Anatomical  Diagnosis. — Congenital  syphilis ;  interstitial  pneumonia ; 
splenic  tumor;  chronic  perisplenitis. 

Microscopic  Examination  of  the  Pancreas. — The  interstitial  tissue  is 
greatly  increased  at  the  expense  of  the  parenchyma,  and  the  lobules, 
composed  of  a  few  acini,  are  irregularly  scattered  in  dense  eeUular 
stroma.  The  smallest  ducts,  beset  with  acini  along  theii'  course,  ter- 
minate in  a  group  of  acini  which,  though  much  less  numerous  than 
those  ordinarily  forming  a  lobule,  are  of  noi'mal  size,  and  are  composed 

'  Schlesinger :  Virehow's  Arch.,  1898,  cliv,  SOL 


252  DISEASE  OF  THE  PANCREAS 

of  cells  showing  no  evidence  of  degeneration.  The  interlobular  tissue 
contains  many  fibroblasts  and  lymphoid  cells;  plasma  cells  are  particu- 
larly numerous  about  the  blood-vessels  and  cells  with  eosinophilic  gran- 
ules are  abundant.  Though  islands  of  Langerhans  are  embedded  in 
the  stroma  which  separates  the  neighboring  acini,  they  are  not  invaded 
by  the  inflammatory  change.  Some  of  these  islands  of  Langerhans 
are  in  continuity  with  the  ducts  of  the  gland  (Fig.  34.)  At  the  periph- 
ery of  the  island  of  Langerhans  one  of  the  columns  projects  beyond 
the  general  circular  outline  and  is  continuous  with  epithelial  cells 
which,  staining  less  brightly  with  eosin,  are  arranged  about  a  lumen  and 
are  in.  turn  continuous  with  adjacent  acini.  Nevertheless,  many  islands 
of  Langerhans,  traced  through  a  series  of  sections,  are  found  com- 
pletely isolated. 

Case  XXV. — An  infant,  50  cm.  in  length,  lived  four  hours. 

Anatomical  Diagnosis. — Congenital  syphilis;  pemphigus  neona- 
torum; interstitial  pneumonia;  interstitial  hepatitis  and  pancreatitis; 
splenic  tumor. 

Microscopic  Examination  of  the  Pancreas. — The  interstitial  tissue 
is  greatly  increased  and  the  parenchyma  is  in  great  part  replaced 
by  it.  The  new  tissue  is  veiy  cellular,  but  the  cells  are  in  great  part 
fibroblast.s,  and  accumulations  of  round  cells  are  not  found.  Plasma 
cells  and  cells  with  eosinophilic  granulations  are  rarely  seen.  The 
acini  form  small  groups  which  may  be  regarded  as  primary  lobules, 
though  the  acini  composing  them  are  much  less  numerous  than  those 
of  a  normal  lobule.  Islands  of  Langerhans  occur  as  compact  round 
masses  of  epithelial  cells  and  are  scattered  abundantly  throughout  the 
organ.  The  fibrous  tissue  is  often  concentrically  arranged  about  these 
interacinar  islands,  and  at  times  they  are  completely  isolated.  Not 
infrequently,  however,  as  in  the  preceding  case,  they  are  in  continuity 
with  the  neighboring  ducts;  a  double  row  of  cells  is  continuous  on  the 
one  hand  with  a  cell-column  of  an  island  of  Langerhans,  on  the  other 
with  a  small  duct.  • 

The  preceding  cases  represent  different  stages  of  the 
syphilitic  lesion.  In  Case  XXIV  cells  which  accumulate 
with  inflammation — namely,  lymphoid  and  plasma  cells 


v^  O  '^QPS^     P^Q-^-^     ^ 


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Fig.  34. — Congenital  syphilitic  pancreatitis  (Case  XXIV).     Showing  a  cell-column  of  an  island 
of  Langerhans  in  continuity  with  a  small  duct. 


TUBERCULOSIS— SYPHILIS  253 

and  eosinophile  leucocytes — are  numerous,  and  the  con 
dition  represents  tlie  active  stage  of  a  chronic  inflanuna- 
tory  process.  In  Case  XXV,  though  interstitial  tissue  is 
more  abundant  and  the  persistent  parenchymatous  ele- 
ments are  more  scattered,  cells  of  lymphoid  type  are  few 
m  number,  while  plasma  cells  and  eosinophiles  are  almost 
absent.  The  process  is  more  advanced  and  is  no  longer 
active. 

A  conspicuous  feature  in  both  cases  is  the  presence 
of  numerous  islands  of  Langerhans  surrounded  by  newly- 
formed  stroma,  but  uninvaded  by  it.  In  many  instances 
the  islands  of  Langerhans  are  in  continuity  with  the 
secreting  structures  of  the  gland  (Fig.  34).  A  cell- 
column  of  the  island  of  Langerhans  is  continuous  with  a 
small  duct,  which  is  in  turn  beset  with  acini ;  ^  the  lumen 
of  the  duct  does  not  penetrate  into  the  island  of  Langer- 
hans, but  disappears  at  its  periphery. 

Birch-Hirschfeld  has  claimed  that  syphilitic  pancrea- 
titis has  its  onset  during  the  last  months  of  fetal  life. 
Schlesinger  cites  cases  of  Miiller  and  Mraczek,  in  which, 
at  the  fifth  month  of  development,  advanced  lesion  of 
the  organ  has  occurred,  and  from  his  own  experience 
concludes  that  the  pancreas  may  be  affected  as  early  or 
as  late  as  other  organs. 

At  an  early  period  of  development — for  example,  dur- 
ing the  fifth  month  of  fetal  life — acini  form  small  groups 
widely  separated  by  embryonic  connective  tissue.  In  the 
two  cases  of  syphilitic  pancreatitis  just  described  the 
parenchyma  has  the  appearance  observed  about  the  fifth 
month  of  development.     Congenital  syphilis  of  the  pan- 

"  Opie :  Jour,  of  Exper.  Med.,  1901,  v,  397. 


254  DISEASE  OF  THE  PANCREAS 

creas,  like  other  syphilitic  lesions,  affects  primarily  the 
interstitial  tissue,  and  changes  in  the  parenchyma  result 
not  so  much  from  destruction  of  the  parenchyma  as  from 
interference  with  its  growth.  Similarity  between  the 
syjihilitic  and  the  undeveloped  organ  may  be  thus  ex- 
plained. Development  of  individual  cells  is  not  retarded, 
and  islands  of  Langerhans  are  the  result  of  early  cell- 
differentiation  ;  but  in  many  instances  islands  of  Langer- 
hans remain  in  continuity  with  tubular  structures  from 
which  they  have  had  their  origin.  Often,  however,  the 
connecting  strand  of  cells  is  no  longer  discoverable,  and 
the  interacinar  islands  resemble  those  ordinarily  found 
at  the  end  of  fetal  development. 

Within  the  newly-formed  stroma  of  the  syphilitic 
pancreas  minute  foci  of  necrosis,  described  as  miliary 
gummata,  have  been  found  occasionally.  In  two  of  the 
cases  recorded  by  Birch-Hirschfeld  such  gummata 
occurred,  and  similar  lesions  have  been  repeatedly  found 
by  other  observers. 

Acquired  Syphilis. — With  acquired  syphilis  the  pan- 
creas may  be  the  seat  of  gummata  and  of  syphilitic  in- 
duration resembling  syphilitic  cirrhosis  of  the  liver. 
From  the  older  literature  of  the  subject  Friedreich  cited 
a  case  of  Rostan;  two  gummata  were  found  in  the  pan- 
creas of  a  man  who  had  had  a  chancre  fourteen  years 
before  death.  In  a  man  thirty-four  years  old  Schlagen 
haufer  ^^  found  scars  on  the  prepuce,  syphilitic  indura- 
tion of  the  testicles  with  gumma  of  the  epididymis,  and 
syphilitic  cirrhosis  of  the  liver ;  the  head  of  the  pancreas 
was  indurated  and  a  broad  zone  of  fibrous  tissue  sur- 

"  Schlagenhauf  er :  Arch.  f.  Derm.  n.  Syph.,  1895,  xxxi,  43. 


TUBERCULOSIS— SYPHILIS  255 

rounded  a  yellow  nodule  with  softened  centre.  There 
were  miliary  gummata  in  the  fibrous  stroma,  endarteritis, 
and  peri-arteritis.  In  a  man  sixty-three  years  of  age 
Thorel "  found  the  pancreas  hard  and  irregularly 
shrunl^en  so  that  it  formed  nodular  masses;  upon  the 
cut  surface  little  glandular  tissue  was  recognizable,  and 
scattered  in  the  sclerotic  stroma  were  small  caseous  gum- 
mata. Truhart  ^^  found  a  lobulated  pancreas  puckered 
by  scar-like  fibrous  tissue  in  a  man  aged  thirty-one  years 
who  had  acquired  syphilis  four  years  before  death;  in 
the  mid-part  of  the  gland  was  a  gummatous  nodule. 

In  a  case  described  by  Drozda  ^^  the  pancreas  was 
represented  by  a  mass  of  indurated  tissue,  in  which 
glandular  structures  were  recognizable  only  in  the  head : 
here  and  there  occurred  caseous  gummata  embedded  in 
the  fibrous  stroma.  The  liver  was  the  seat  of  syphilitic 
cirrhosis  and  the  stomach  contained  an  indurated  scar. 
In  a  case  of  visceral  syphilis  described  by  Chvostek  ^*  the 
tail  of  the  pancreas  was  penetrated  by  several  sclerotic 
bands  of  tissue,  giving  it  a  lobed  appearance. 

In  the  cases  which  have  been  cited  changes  are  analo- 
gous to  syphilitic  lesions  of  the  liver  and  are  character- 
ized by  the  occurrence  of  gummata  or  irregular  scar-like 
bands  of  tissue  penetrating  the  parenchyma ;  they  differ 
from  the  more  common  lesion  of  chronic  interstitial  pan- 
creatitis with  which  there  is  a  diffusely  distributed  in- 
crease of  the  interlobular  or  interacinar  tissue. 

In  two  cases  of  chronic  interstitial  pancreatitis  asso- 

"  Thorel :  Cited  by  Truhart. 

"  Loc.  cit.,  p.  viii. 

"Drozda:    Wedner  med.  Presse,  1880,  xxi,  993. 

"  Loc.  cit.,  p.  250. 


256  DISEASE  OF  THE  PANCREAS 

ciated  with  diabetes  Hansemann  obtained  evidence  of 
syphilis.  Kasahara  examined  the  pancreas  in  six  cases 
of  acquired  syphilis,  and  in  two  found  a  moderate  in- 
crease of  the  interstitial  tissue,  in  two  merely  thickening 
of  the  blood-vessels,  and  in  two  no  alterations.  These 
writers  have  believed  that  syphilis  is  a  common  cause  of 
chronic  pancreatitis.  There  was  a  history  of  syphilis 
in  only  one  of  thirty  cases  of  chronic  pancreatitis  which 
I  examined  and  in  this  instance  chronic  inflammation  was 
caused  by  carcinoma  compressing  the  duct  of  Wirsung. 
Syphilis  is  doubtless  a  cause  of  chronic  inflammation  of 
the  gland,  and  the  cases  of  Droza,  Chvostek  and  others 
indicate  the  existence  of  syphilitic  pancreatitis  character- 
ized by  scar-like  bands  of  tissue  which  may  contain 
gummata.  The  etiological  relationship  of  syphilis  to 
a  diffusely  distributed  interacinar  or  interlobular  inflam- 
mation is  doubtful. 


CHAPTER  XI. 


PANCREATIC    CALCULI. 


Panceeatic  lithiasis,  unlike  cholelithiasis,  is  rarely 
found  at  autopsy  and  among  fifteen  hundred  autopsies 
at  the  Johns  Hopkins  Hospital  occurred  only  twice. 
Gall-stones  are  usually  formed  within  the  gall-bladder, 
whereas  pancreatic  calculi  are  formed  within  the  ducts 
of  the  gland.  The  disease  is  more  common  in  men  than 
in  women;  of  fifty-seven  cases  collected  by  Lazarus^ 
forty-seven  were  in  men  and  ten  in  women,  thirty-seven 
occurring  between  the  ages  of  thirty  and  forty  years. 

Pathological  Anatomy. — Concretions  within  the  ducts 
may  resemble  fine  sand,  but  usually  there  are  one  or  more 
small  stones,  sometimes  as  many  as  a  hundred.  The 
largest  calculus  which  has  been  described  (Schupp- 
mann  ^)  measured  one  and  a  half  inches  across.  Concre- 
tions are  usually  hard  and  white,  or  grayish  white,  and 
consist  in  great  part  of  calcium  carbonate  and  phosphate, 
together  with  other  inorganic  salts.  Two  analyses  by 
Johnston  ^  are  as  follows :  Case  I. — Calcium  phosphate, 
72.3  per  cent. ;  calcium  carbonate,  18.9  per  cent. ;  organic 
matter,  8.8  per  cent.  Case  II. — Calcium  carbonate,  91.65 
per  cent. ;  magnesium  carbonate,  4.15  per  cent. ;  organic 
matter,  3  per  cent.     Calculi  containing  cholesterin  in  con- 

^  Lazarus :  Beitrag  zur  Pathologie  and  Therapie  der  Pankreas- 
erkrankungen  mit  besonderer  Beriieksiehtigung  der  Cysten  und  Steine. 
Berlin,  1904. 

^  Schuppmann :  Hufeland's  Jour.,  1841,  xcii,  41.     Quoted  by  Oser. 

*  Johnston :  American  Jour,  of  the  Med.  Scien.,  1883,  Ixxxvi,  404. 
17  257 


258  DISEASE  OF  THE  PANCREAS 

siderable  amount  have  been  found  and  Shattock  ^  has  re- 
moved from  a  pancreatic  cyst  a  calculus  consisting  almost 
wholly  of  calcium  oxalate. 

Biliary  calculi  occasionally  make  their  way  into  the 
pancreatic  ducts  (Dieckhoff)  and  their  presence  has  been 
associated  with  pancreatic  suppuration.  A  pancreatic 
calculus  lodged  at  the  duodenal  end  of  the  bile  duct  may 
be  stained  by  bile  pigments  and  receive  a  layer  of  choles- 
terin  (Robson  and  Cammidge). 

The  duct  of  Wirsung  is  narrower  than  elsewhere  at  its 
duodenal  termination  where  it  passes  through  the  duo- 
denal wall,  and  calculi  tend  to  lodge  above  this  point. 
The  outflow  of  secretion  may  be  completely  prevented 
and  the  duct  may  be  dilated  behind  the  obstruction. 
True  cysts  are  rarely  formed  but  Von  Recklinghausen  ^ 
has  described  a  cyst  the  size  of  a  child's  head  apparently 
caused  by  a  calculus  impacted  at  the  end  of  the  pancreatic 
duct. 

Occlusion  of  the  duct  by  calculi  causes  changes  similar 
to  those  which  follow  experimental  ligation  of  the  duct 
in  animals  and,  usually  associated  with  bacterial  infec- 
tion, produces  the  most  advanced  sclerosis  to  which  the 
gland  is  subject.  Chronic  inflammation  is  interlobular 
in  type  and  tends  to  spare  the  islands  of  Langerhans ;  the 
following  cases  illustrate  the  changes  which  occur  in  the 
pancreas : 

Case  XXVI. — Summan/  of  Clinical  History. — W.  H.,  male,  aged 
forty-three  years,  was  admitted  to  the  Johns  Hopkins  Hospital  suffer- 
ing with  pulmonary  tuberculosis.     lie  had  used  beer  in  large  quantity. 

*  Shattock :  British  Med.  Jour.,  1896,  i,  1034. 

"Von  Recklinghausen:    Virehow's  Arch.,  1864,  xxx,  360. 


PANCREATIC  CALCULI  259 

Ten  months  before  his  death  he  had  had  an  attack  of  jaundice.     No 
symptoms  of  diabetes  were  noted. 

Anatomical  Diagnosis. — Chronic  puhnonary  tuberculosis;  tuber- 
culous pleurisy.  Cirrhosis  of  the  liver  with  fatty  degeneration: 
Splenic  tumor.  Pancreatic  calculi;  interstitial  pancreatitis;  peripan- 
creatic  fat  necrosis,  ■'• 

Pancreas. — The  duet  of  Wirsung  and  its  branches  are  much  tJis- 
tended  by  numerous  calculi,  which  give  the  reactions  of  calcium  car- 
bonate. Glandular  tissue  has  in  large  part  disappeared,  and  is^rei- 
placed  by  interstitial  tissue  containing  abundant  fat,  in  which  are 
opaque,  white  areas  of  necrosis.  ':■■... 

Microscopic  Examination. — The  parenchyma  has  been  in  very  great 
part  replaced  by  dense  fibrous  tissue,  in  which  are  scattered  foci  .of 
round  cells.  In  the  head  of  the  organ  are  small  areas  of  glandujajc 
tissue,  subdiArided  by  interlobular  fibrous  strands.  Occasionally  lobul.es 
are  found  in  process  of  disintegTation,  atrophied  acini  with  dilated 
lumen  being  separated  by  newly-formed  interstitial  tissue.  Numerous 
islands  of  Langerhans,  most  abundant  in  a  section  from  the  splenic 
end  of  the  organ,  are  surrounded  and  isolated  by  newly-formed  stroiiiS; 
and  though  the  tissue  about  is  densely  fibrous,  within  the  islands  are 
delicate  capillaries,  often  distended  with  red  blood-corpuscles.  Occa- 
sionally an  island  has  the  appearance  of  being  compressed  and  distorted. 

Case  XXVII. — Summary  of  Clinical  History. — The  patient,  male, 
aged  fifty  years,  had  used  alcohol  in  excess.  His  illness  began  flye 
months  before  its  fatal  termination  with  symptoms  of  pulmonary 
tuberculosis  gradually  increasing  in  severity.  On  admission  to  the 
Hospital,  two  months  after  the  onset  of  his  illness,  the  urine  contained 
5.2  per  cent,  of  sugar.  When  given  a  diet  poor  m  carbohydrates  (Vonj 
Noorden's  standard  diabetic  diet),  sugar  disappeared  from  the  urinej 
and  reappeared  only  when  carbohydrates  were  added, — 90  Gm.  of  white 
'  bread  to  the  daily  diet.  . 

Anatomical  Diagnosis. — Pancreatic  calculi;  chronic  interstitial  pan- 
creatitis; parapanereatie  fat  necrosis.  Chronic  pulmonary  tuberculosis.' 
Chronic  diffuse  nephritis;  large  white  kidneys.  Anthraeosis  of  lungs, 
spleen,  and  kidneys.  '■  •• 

Pancreas.— The  organ  is  much  diminished  in  size  and  is  tough  and 


260  DISEASE  OF  THE  PANCREAS 

fibrous.  Atrophy  is  so  marked  that  the  body  is  merely  a  narrow 
isthmus  connecting  the  head  and  tail.  The  duct,  slightly  enlarged, 
contains  viscid  white  fluid  and  a  number  of  gritty,  yellow  calculi,  the 
largest  being  the  size  of  a  split  pea.  On  section  the  tissue  has  a 
grayish-yellow  color,  and  small  masses  of  parenchyma  project  between 
thick  bands  of  connective  tissue.  Minute  opaque  points  suggest  fat 
necroses. 

Microscopic  Examination. — Sclerosis  is  far  advanced  and  is  most 
marked  in  the  tail  of  the  organ,  where  glandular  acini  are  almost 
entirely  absent.  The  glandular  tissue  which  stiU  persists  occurs  as 
small,  compact  masses  embedded  in  dense  stroma.  At  the  periphery 
of  this  relatively  normal  parenchyma  are  lobules  or  parts  of  lobules 
undergoing  disintegration  and  replacement  by  interstitial  tissue.  Com- 
pletely isolated  in  the  dense  stroma  of  the  body  and  tail  are  numerous 
masses  of  polygonal  cells  occupying  conspicuous,  sharply  outlined, 
tound  or  oval  spaces  in  the  sclerotic  tissue.  These  islands  of  Langer- 
hans  are  so  thickly  scattered  that'  in  places  ten  or  twelve  may  be  seen 
in  the  field  of  the  low  power.  In  the  surrounding  tissue  lymphoid  and 
plasma  cells  are  numerous. 

Such  persistent  islands  of  Langerhans  are  finally  implicated  in  the 
general  sclerosis.  An  increase  of  fibrous  tissue  occurs  along  their 
capillaries,  which  become  coai'se  strands  subdividing  the  body  into 
small  masses  of  atrophied  cells.  Elsewhere  broad  bands  of  dense  fibrous 
tissue  contain  no  epithelial  elements  or  only  an  occasional  compressed 
group  of  cells  similar  to  those  which  form  the  islands  of  Langerhans. 

In  Case  XXVII  the  lesion  is  far  advanced,  acini  are 
in  large  part  destroyed  and  islands  of  Langerhans  are  in 
part  destroyed,  in  part  hypertrophied ;  there  has  been 
glycosuria,  disappearing  under  appropriate  treatmei^t. 
In  a  similar  case  of  Lazarus  changes  affecting  the  islands 
of  Langerhans  have  been  associated  with  glycosuria. 

Obstruction  to  the  outflow  of  pancreatic  juice  may 
cause  its  escape  into  surrounding  tissues  and  fat  necrosis 
may  result  (Case  XXVI).    New  formation  of  fibrous  tis- 


PANCREATIC  CALCULI  261 

sue  doubtless  inhibits  escape  of  products  of  secretion. 
Passage  of  calculi  through  the  diverticulum  of  Vater 
may  occlude  the  common  bile  duct  and  cause  jaundice 
(perhaps  in  Case  XXVI) ;  Gould  "^  has  observed  jaundice 
caused  by  lodgement  of  a  pancreatic  calculus  in  the 
diverticulum  of  Vater. 

With  calculi  there  is  usually  bacterial  infection  which 
is  perhaps  the  cause  of  lithiasis  or,  it  may  be,  the  result 
of  obstruction  to  the  outflow  of  pancreatic  juice.  Pres- 
sure of  the  stone  within  a  duct  may  cause  ulceration  of 
the  mucous  membrane.  Such  conditions  favor  the  occur-' 
rence  of  acute  inflammation  and  pancreatic  abscess  may 
accompany  stone.  ': 

The  etiology  of  pancreatic  lithiasis  is  obscure.  Asso- 
ciated bacterial  infection  is  probably  an  etiological  factor 
and  Giudiceandrea  ^  has  found  a  variety  of  bacterial 
forms  within  pancreatic  calculi.  Obstruction  to  the  out- 
flow of  pancreatic  juice  may  favor  the  formation  of  cal- 
culi. Pancreatic  lithiasis  occurs  in  association  with 
cholelithiasis  (Dieckhoff,  Lazarus)  and  may  perhaps  foi-- 
low  temporary  obstruction  of  the  pancreatic  ducts  by- 
passing calculi.  The  occurrence  of  calculi  in  pancreatic 
cysts  suggests  that  the  retained  secretion  affords  those 
conditions  which  are  necessary  for  formation  of  concre- 
tions; Lazarus  describes  four  instances  in  which  cysts 
contained  calculi  at  times  in  considerable  number. 

Little  success  has  attended  efforts  to  produce  experi- 
mentally  pancreatic   calculi.     Thiroloix*    and   Lazarus 

'  Gould :  British  Med.  Jour.,  1898,  ii,  1816. 

'Giudiceandrea:    Policlinieo,  1896,  iii-M,  33,  126;    Bull.  d.  See. 
Laneisiana  d.  osp.  di  Roma,  1897-8,  xviii,  119. 

'Thiroloix:  Thesis,  Paris,  1892.  ...  - 


262-  DISEASE  OF  THE  PANCREAS 

have  found  small  concretions  within  cysts  produced  by 
injury  to  the  pancreas. 

Symptoms. — Pancreatic  calculi  may  be  found  at 
autopsy  in  individuals  who  have  not  suffered  with  local 
symptoms  referable  to  pancreatic  disease;  densely  scle- 
rotic pancreas  surrounded  numerous  jagged  stones  in  an 
individual  who,  dying  with  diabetes,  had  had,  according 
to  Lazarus,  no  epigastric  jDain.  Pain  in  association  with 
pancreatic  lithiasis  may  be  slight  and  continued,  but 
more  characteristic  are  paroxysms  of  pain  resembling 
biliary  colic  and  accompanied  perhaps  by  vomiting  and 
collapse,  at  times  with  chills  and  fever.  Leichtenstern '^ 
observed  such  symptoms  unaccompanied  by  jaundice  in 
a  patient  who  evacuated  from  the  rectum  three  concre- 
tions composed  of  calcium  carbonate  and  free  from  bile 
pigments  or  cholesterin.  In  a  case  described  by  Lich- 
theim  ^"  attacks  of  severe  epigastric  pain  recurred  during 
eight  years ;  after  an  interval  of  six  years  the  patient  died 
with  diabetes  and  pancreatic  calculi  were  found.  Colic- 
like pain  in  the  epigastrium  may  be  more  marked  on  the 
left  side  but  its  localization  is  not  characteristic. 

Jaundice  with  pancreatic  calculi  may  be  caused  by 
coexisting  gall-stones.  A  pancreatic  calculus  passing 
into  the  duodenum  may  occlude  the  common  bile  duct  and 
cause  jaundice.  In  a  case  described  by  Leichtenstern 
autopsy  demonstrated  the  occurrence  of  pancreatic  cal- 
culi without  cholelithiasis;  the  patient  had  had  attacks 
o£  severe  abdominal  pain,  once  accompanied  by  jaundice. 

Diabetes  mellitus   or   glycosuria   frequently  accom- 


••"Leichtenstern:  Handb.   der   spec.    Tlicr.   von   Penzoldt-Stintzing, 
1896,  iv,  618. 

"  Lichtheim :  Berliner  klin.  Woch.,  1894,  xxxi,  185. 


PANCREATIC  CALCULI  263 

panies  pancreatic  lithiasis  and  has  been  present  in  thirty- 
six  of  eighty  cases  collected  by  Lazarus;  nevertheless, 
only  a  small  proportion  of  cases  of  diabetes  mellitus  is 
referable  to  calculi.  Disturbance  of  carbohydrate  metab- 
olism is  caused  not  by  occlusion  of  the  pancreatic  ducts 
but  by  the  consequent  chronic  interlobular  pancreatitis 
and  occurs  only  when  the  lesion  is  so  far  advanced  that 
the  islands  of  Langerhans  are  in  part  destroyed.  In  the 
case  of  Lichtheim  diabetes  mellitus  had  made  its  appear- 
ance thirteen  years  after  the  first  attack  of  severe  ab- 
dominal pain  and  in  the  case  of  Caparelli^^  six  years 
after  onset.  Alimentary  glycosuria  present  in  Case 
XXVII  and  in  cases  of  Lichtheim,  of  Lazarus,  and  of 
Keuthe  ^^  indicates  a  less  advanced  stage  of  the  pancre- 
atic lesion.  In  cases  of  Polyakoff  ^^  and  of  Minnich  ^^ 
there  has  been  transient  glycosuria  following  attacks  of 
colic. 

Steatorrhoea  when  present  has  much  significance  for 
diagnosis,  but  has  been  recorded  in  only  ten  of  the  eighty 
cases  collected  by  Lazarus.  Chemical  analysis  in  cases 
of  Miiller  ^^  and  of  Kinnicutt  ^^  showed  a  diminished 
proportion  of  split  fat  in  the  faeces,  although  the  total 
fat  was  not  notably  increased. 

Azotorrhoea  is  less  frequently  observed  than  fatty 
stools ;  in  the  case  of  Lichtheim  undigested  muscle  fibres 
were  found  in  the  fasces. 

''  Caparelli :  II  Morgagni,  1883,  Ref .  Virehow-Hirsch  Jahresb., 
1883,  ii,  267. 

''Keuthe:    Berliner  klin.  Woch.,  1909,  Ivi,  47. 

"  PolyakofE :  Berliner  klin.  Woeh.,  1898,  xxxv,  237. 

"  Minnich :  Berliner  klin.  Woch.,  1894,  xxxi,  187. 

''  Miiller :   Loc.  cit.,  p.  92. 

'"  Kinnicutt :  American  Jour,  of  the  Med.  Scien.,  1902,  cxxiv,  948. 


264  DISEASE  OF  THE  PANCREAS 

Diagnosis  of  pancreatic  lithiasis  has  been  made  by 
discovery  of  pancreatic  calculi  either  in  the  faeces  or  in 
the  discharge  from  a  pancreatic  fistula.  Kinnicutt  ^^  has 
collected  seven  cases  which  have  been  recognized  during 
life;  in  three  instances  diagnosis  has  been  made  by  find- 
ing in  the  fasces  after  attacks  of  colic  calculi  composed  in 
great  part  of  calcium  phosphate  and  carbonate  without 
bile  salts  or  other  peculiar  constituents  of  bile. 

In  the  case  of  Lichtheim  attacks  of  colic  repeated  dur- 
ing many  years  were  unaccompanied  by  jaundice,  and  the 
occurrence  of  diabetes  mellitus  suggested  that  the  pan- 
creas was  the  seat  of  disease.  Robson  and  Cammidge 
have  found  pancreatic  calculi  more  opaque  for  X-rays 
than  gall-stones,  and  have  proposed  the  use  of  X-rays 
for  diagnosis.  Suppuration  may  occur  as  a  complication 
of  pancreatic  lithiasis.  In  a  case  of  Caparelli  an  abscess 
in  the  epigastric  region  discharged  over  a  hundred  pan- 
creatic calculi.  In  a  case  described  by  Nicholas  and 
Molliere  ^^  hemorrhage  from  the  bowel  twice  followed 
rupture  into  the  duodenum  of  an  abscess  caused  by  pan- 
creatic calculi. 

Treatment. — Conditions  which  increase  the  flow  of 
jDancreatic  juice  are  believed  to  aid  in  overcoming  ob- 
struction caused  by  calculi  and  to  hinder  their  formation. 
Secretion  may  be  increased,  according  to  Lazarus,  by 
administration  of  water  in  abundance  especially  when 
acidified  by  carbonic  gas  or  by  a  weak  acid.  The  use 
of  pilocarpin,  which  has  been  suggested,  is  perhaps  not 
without  danger,   since  its   administration  to  cats  with 

"  Kinnicutt :    Trans.  Assoc.  American  Phys.,  1902,  xvii,  81. 
"  Nicolas  and  Molliere :  Bull,  nied.,  1897. 


PANCREATIC  CALCULI  265 

ligated  pancreatic  ducts  has  rapidly  caused  death.     (See 
Experiment  X,  Chap.  VII.) 

In  several  cases  pancreatic  calculi  have  been  success- 
fully removed  by  operation.  Gould  ^^  opened  the  ab- 
dominal cavity  of  a  patient  with  symptoms  suggesting 
cholelithiasis  and  found  a  lump  at  the  posterior  part  of 
the  lesser  peritoneal  cavity,  and  by  incision  removed  a 
calculus  from  the  duct  of  Wirsung;  biliary  obstruction 
continued  and  at  a  second  operation  another  calculus  was 
removed  from  the  head  of  the  pancreas.  Death  with 
suppuration  occurred  twelve  days  later.  Moynihan  ^'^ 
removed  through  the  duodenum  a  calculus  projecting 
from  the  duct  of  Wirsung  into  the  diverticulum  of  Vater ; 
recovery  followed.  Eobson  and  Cammidge  cite  a  similar 
successful  operation  of  Dalziel  and  record  a  case  in 
which  recovery  has  followed  the  removal  of  four  pancre- 
atic calculi.  One  of  these  calculi  has  been  removed  from 
the  duct  of  Santorini  or  one  of  its  branches  through  an 
incision  into  the  pancreas  near  the  common  bile  duct; 
two  have  been  removed  from  the  duct  of  Wirsung  by  deli- 
cate forceps  introduced  through  an  incision  into  the 
duodenum  opening  the  bile  papilla ;  and  a  fourth  has  been 
removed  from  the  midpart  of  the  duct  of  Wirsung  after 
cutting  through  the  gastrohepatic  omentum  and  incising 
the  pancreas  over  the  stone.  Staehlin  and  Roeber  ^i  cut 
into  the  head  of  the  pancreas  and  removed  several  cal- 
culi from  the  duct  of  Wirsung ;  recovery  followed. 

'"  Gould,  P. :  Lancet,  1898,  ii,  1632. 

'"Moynihan:  Lancet,  1902,  ii,  355. 

'^  Staehlin  and  Roeber :  New  York  Med.  Jour.,  1905,  Ixxxii,  904. 


CHAPTER  XI r. 


CYSTS. 


True  cysts  of  the  pancreas  are  formed  when  obstruc- 
tion to  outflow  of  pancreatic  secretion  causes  retention  of 
fluid  and  dilatation  of  duets  or  of  acini  (retention  cysts), 
or  when  spontaneous  ])roliferation  of  the  epithelial  ele- 
ments of  the  gland  is  followed  l)y  accumulation  of  fluid 
in  cavities  which  are  formed  (cystic  tumors).  A  large 
proportion  of  so-called  pancreatic  cysts  on  the  contrary 
have  no  epithelial  lining  l)ut  are  cavities  (pseudocysts) 
containing  fluid  surrounded  by  a  wall  of  connective  tissue, 
formed  within  the  pancreas  or  in  contact  with  its  surface. 
The  formation  of  such  pseudocysts,  which  do  not  occur 
in  other  glands,  is  dou])tless  dependent  upon  the  peculiar 
properties  of  the  pancreatic  juice,  and  their  contents  arc 
in  part  at  least  products  of  pancreatic  secretion. 

Retention  Cysts. — Ligation  of  pancreatic  ducts  in  ani- 
mals causes  chronic  inflammation  of  the  gland  with  little 
dilatation  of  the  duct  l)eliind  the  occlusion;  obstruction 
to  the  outflow  of  secretion  in  man  is  usually  followed  by 
similar  changes.  Nevertheless,  under  conditions  which 
are  not  understood,  cysts  occur  as  the  result  of  such  ob- 
struction ;  it  has  been  suggested  that  partial  or  intermit- 
tent occlusion  may  favor  their  formation.  Such  cysts 
are  usually  small  and  do  not  cause  recognizable 
symptoms.  Virchow  ^  descril)ed  as  ranula  pancreatica 
dilatation  of  the  duct  of  Wirsung  caused  by  occlusion; 
numerous  sacculations  may  give  the  duct  a  beaded  ap- 

'  Virchow:  Die  kranldiaften  Geschwulsto,  Berlin,  18G3,  ii,  276. 
266 


^'CYSTS  267 

pearance  or  there  may  be  a  single  cystic  dilatation  per- 
haps as  large  as  a  man's  fist.  Klebs  ^  gave  the  name 
acne  pancreatica  to  multiple  cysts  of  small  size  containing 
opaque  thick  fluid;  such  small  cysts  are  formed  from 
small  ducts  or  even  from  acini. 

Compression  of  the  pancreatic  ducts  by  tumor,  by  gall- 
stones, or  by  pancreatic  calculi  is  usually  unaccompanied 
by  cyst  formation  but  occasionally  multiple  cysts  result; 
the  following  case  illustrates  cyst  formation  as  a  sequel 
of  tumor  compressing  the  duct  of  Wirsung. 

Case  XXVIII. — The  patient,  female,  aged  forty-one  years,  became 
jaundiced  nine  months  before  her  death.  A  tumor  mass  was  palpable 
in  the  umbilical  region. 

Anatomical  Diagnosis. — Adenocarcinoma  of  the  pancreas  com- 
pressing the  bile  and  jDancreatic  ducts;  jaundice;  chronic  interlobular 
pancreatitis;  retention  cysts  of  the  pancreas;  metastatic  carcinoma  of 
the  retroperitoneal  lymph-glands. 

The  tumor,  which  arises  from  the  pancreas,  consists  of  two  masses 
between  which  the  remains  of  the  head  and  part  of  the  body  of  the 
gland  lie  compressed.  A  fibrous  capsule  separates  the  tumor  from  the 
glandular  parenchyma.  Numerous  small  cysts  of  which  the  largest 
are  about  2.5  cm.  in  diameter  occupy  the  body  and  tail  and  are  present 
but  less  numerous  in  the  duodenal  end  of  the  gland.  A  probe  can  be 
passed  along  the  compressed  duct. 

Microscopic  examination  shows  throughout  the  gland  a  moderate 
increase  of  the-  interstitial  tissue  between  the  lobules  and  in  slight 
degree  within  them.  Cysts  lined  by  a  single  layer  of  cubical  or  flat 
epithelium  are  abundant  in  the  body  and  tail.  The  larger  cysts  are 
surrounded  by  a  layer  of  sclerotic  connective  tissue  in  which  a  few 
isolated  and  compressed  islands  of  Langerhans  are  the  only  remains 
of  pancreatic  parenchyma.  Elsewhere  these  bodies  are  fairly  abundant 
and  noraial  in  structure. 

'Klebs:  Handbuch  der  pathologisehen  Anatomie,  Berlin,  1868,  i. 


268  DISEASE  OF  THE  PANCREAS 

Cysts  occasionally  of  large  size  have  been  associated 
with  gall-stones  lodged  near  the  orifice  of  the  pancreatic 
duct  (Plmlpin,^  Horrocks  and  Morton^);  a  pancreatic 
calculus  has  been  found  near  the  end  of  the  duct  of  Wir- 
sung  (Von  Eecklinghausen),  but  its  relationship  to  cyst- 
formation  is  not  obvious,  for  it  is  probable  that  concre- 
tions may  be  formed  within  such  cysts. 

Chronic  pancreatitis  has  been  regarded  by  Tilger  ° 
as  an  important  factor  in  the  production  of  pancreatic 
cyst,  for,  he  has  thought,  scar-like  bands  of  connective 
tissue  compress  and  occlude  ducts.  Chronic  pancreatitis 
on  the  contrary  may  be  secondary  to  cyst-formation ;  by 
compression  of  neighboring  ducts  cysts  cause  chronic  in- 
flammation. Outside  of  the  epithelial  lining,  which  is 
composed  of  a  single  laj^er  of  cylindrical  cells  often  flat- 
tened by  pressure,  a  wall  of  dense  fibrous  tissue  is  formed. 
Occlusion  of  ducts,  which  may  be  either  the  cause  or  the 
result  of  cyst-formation,  is  always  followed  by  interlobu- 
lar pancreatitis,  and  when  this  lesion  implicates  the  entire 
gland  and  is  far  advanced  diabetes  mellitus  ensues. 

Proliferation  Cysts. — The  structure  of  a  small  number 
of  pancreatic  cysts  furnishes  evidence  that  they  arise  as 
true  tumors.  It  is  doubtful  if  the  presence  of  small  cysts 
in  the  wall  of  a  large  cyst  or  the  presence  of  an  occa- 
sional papillary  projection  from  its  inner  surface  is  proof 
that  the  cyst  is  formed  by  proliferation  of  epithelial 
structures,  but  the  occurrence  of  irregular  gland-like 
growths  below  the  epithelial  lining,  and  the  presence  of 
papillary  projections  from  the  lining  into  the  cyst,  serve 
to  demonstrate   spontaneous  proliferation.     Such   cyst- 

'  Phulpin :  Bull,  de  la  Soc.  anat.  de  Paris,  1892,  Ixvii. 
*  Horrocks  and  Morton :    Lancet,  1897,  i,  242. 
•Tilger:    Virehow's  Arch.,  1894,  cxxxvii,  348. 


CYSTS  269 

adenomata  may  resemble  the  similar  tumors  of  the  ovary. 
Korte  has  collected  from  the  literature  of  the  subject  only 
thirteen  instances  of  cystadenomata  and  Miinzer^  (1903) 
has  found  five  additional  cases.  Of  nine  proliferation 
cysts  collected  by  Fitz  ^  eight  occurred  in  women.  Cystic 
tumors  of  the  pancreas  have  rarely  been  malignant. 
Hartmann  ^  has  described  epithelioma  cysticum  of  the 
tail  of  the  pancreas  accompanied  by  metastases  in  the 
liver  and  cites  a  similar  case  of  Hanot  and  Gilbert.  Un- 
der the  name  adenocystoma  papilliferum  Sotti^  has  de- 
scribed a  tumor  of  the  pancreas  which  has  formed  metas- 
tases in  the  lymphatic  glands  and  in  the  lungs  and  by 
implantation  upon  the  peritoneal  surfaces  has  produced 
secondary  nodules  resembling  those  which  occur  with 
similar  tumors  of  the  ovary. 

Pseudocysts. — So-called  pseudocysts  may  be  formed 
within  the  substance  of  the  pancreas  as  the  result  of  de- 
generative changes  aifecting  the  interstitial  tissue  of  the 
gland,  and  their  formation  and  increase  in  size  is  doubt- 
less dependent  in  large  part  upon  the  presence  of  the 
irritant  and  corrosive  products  of  pancreatic  secretion. 
When  the  surface  of  the  pancreas  is  implicated  similar 
cysts  may  be  formed  in  contact  with  the  gland,  and  a  very 
large  proportion  of  all  so-called  pancreatic  cysts  occupy 
the  lesser  peritoneal  cavity.  The  wall  of  such  cysts  is 
formed  by  dense  connective  tissue  of  variable  thickness. 
There  is  no  epithelial  lining,  but  the  absence  of  epithelium 

'  Miinzer :  Pankreaseysten,  Cent,  f .  d.  Grenz.  d.  Med.  u.  Chir.,  1903, 
vi,  490,  529,  573,  619,  664. 

''  Fitz :    Trans.  Assoc,  of  American  Phys.,  1900,  xv,  254. 

*  Hartmann:    Cong,  frang.  de  chir.,  1891,  v,  618. 

*  Sotti :  Arch,  per  le  sc.  med.,  1906.  Ref .,  Cent,  f .  allg.  Path.  u. 
path.  Anat,  1907,  xviii,  844. 


270  DISEASE  OF  THE  PANCREAS 

does  not  determine  the  nature  of  the  lesion,  for  the  lining- 
of  cysts  arising  as  the  result  of  occlusion  of  ducts  or  of 
epithelial  proliferation  may  be  destroyed  by  the  cor- 
rosive action  of  the  cystic  contents. 

Cysts  containing  blood  have  been  believed  to  arise  as 
the  result  of  hemorrhage  into  the  pancreas,  and  apoplec- 
tic cysts  have  been  described,  but  hemorrhage  from 
dilated  and  injured  blood-vessels  occurs  into  cysts 
of  the  pancreas  as  into  Gjnts  of  other  organs.  Never- 
theless, clinical  and  experimental  evidence  proves 
that  cysts  may  be  formed  as  the  result  of  injuries  which 
cause  localized  hemorrhage.  Lazarus  ^"^  has  produced 
small  cysts  by  crushing  the  pancreas  of  the  dog.  In  one 
instance  a  hajmatoma  has  been  the  immediate  result,  and 
at  the  end  of  forty  days  a  cyst  with  fibrous  capsule, 
containing  100  c.c.  of  watery  fluid  has  been  found ;  prod- 
ucts of  pancreatic  secretion,  according  to  Lazarus,  have 
digested  injured  tissue  and  blood. 

In  thirty-three  of  one  hundred  and  seventeen  instances 
of  pancreatic  cyst  Korte^^  has  found  that  abdominal  in- 
jury preceded  the  appearance  of  a  palpable  tumor ;  eight 
additional  cases  have  been  collected  by  Lazarus  (1904). 
There  has  been  injury  limited  to  the  epigastric  region, 
such  as  the  kick  of  a  horse  or  compression  between  the 
buffers  of  two  cars.  To  show  that  indirect  force  may 
cause  pancreatic  cyst,  Lazarus  cites  cases  in  which  cyst 
has  followed  a  violent  fall,  and  suggests  that  the  weight 
of  the  filled  transverse  colon  may  tear  the  movable  splenic 
from  the  fixed  duodenal  i)art  of  the  gland. 

'"Loc.  cit.,  p.  257. 
"  Loc.  cit.,  y>.  viii. 


CYSTS  271 

So-called  traumatic  cysts  usually  contain  blood  but 
evidence  of  hemorrhage  may  be  entirely  absent,  the  cyst 
containing  clear  fluid.  In  a  case  described  by  Richard- 
son ^^  the  ruptured' pancreatic  duct  opened  within  the 
cyst,  appearance  of  which  had  followed  injury  in  the 
epigastrium.  In  the  contents  of  traumatic  cysts  enzymes 
similar  to  those  of  the  pancreatic  juice  have  been  found. 

The  formation  of  cysts  as  a  sequel  of  hemorrhagic 
necrosis  of  the  pancreas  is  proved  by  a  number  of  re- 
corded cases. 

In  a  case  of  Francke  ^^^  sudden  appearance  of  intense 
epigastric  pain  with  vomiting  suggested  the  onset  of 
hemorrhagic  necrosis ;  two  weeks  later  a  tumor  was  pal- 
pable in  the  left  hypochondriac  region,  and  five  weeks 
after  onset  of  symptoms  a  thin-walled  cyst  the  size  of  a 
man's  head  was  found  in  the  lesser  peritoneal  cavity. 
The  pancreas  was  the  seat  of  necrosis  and  old  hemor- 
rhage, and  the  omentum  and  mesentery  contained  foci  of 
fat  necrosis.  Rasumosky  ^^  has  described  a  similar  case 
in  which  a  tumor  mass  appeared  in  the  epigastrium  five 
hours  after  onset  of  symptoms ;  a  cyst  containing  necrotic 
pancreatic  tissue  was  found  at  operation  three  weeks 
later.  Adler  ^^  has  described  a  pseudocyst  which  proba- 
bly followed  hemorrhagic  necrosis  of  the  pancreas.  In 
a  case  of  hemorrhagic  necrosis  of  the  pancreas  described 
by  Dressel  ^^  there  was  a  cavity  the  size  of  a  child's  head 
within  the  substance  of  the  pancreas;  it  was  filled  with 

''  Richardson :  Boston  Med.  and  Surg.  Jour.,  1895. 
"  Francke :    Deutsche  Beit,  f .  Chir.,  1900,  liv,  399. 
"  Ra.sumosky :  Langenbeek's  Arch.,  1899,  lix,  565. 
^ Adler:  Virchow's  Arch.,  1904,  Supph  to  clxxvii,  154. 
"Dressel:  Inaug.  Diss.,  Giessen,  1897. 


272  DISEASE  OF  THE  PANCREAS 

clotted  blood.  Necrotic  tissue  and  blood  are  doubtless 
subjected  to  the  solvent  action  of  enzymes  contained  in 
the  pancreatic  secretion  and  fibrous  tissue  is  formed  in 
the  wall  of  the  cavity.  The  changes  which  occur  in  such 
cases  are  doubtless  identical  with  those  which  produce 
traumatic  cysts. 

Contents. — The  character  of  the  fluid  within  pan- 
creatic cysts  furnishes  little  evidence  concerning  the 
origin  of  the  lesion.  Blood  is  usually  present  and  may 
have  undergone  changes  which  render  it  brownish,  coffee- 
colored,  greenish,  or  even  black;  after  absorption  of 
blood  traumatic  cysts  on  the  one  hand  may  contain  clear 
fluid,  whereas  cysts  caused  by  retention  on  the  other  hand 
may  contain  bloody  fluid  as  the  result  of  erosion  or  rup- 
ture of  the  dilated  blood-vessels  in  the  wall  of  the  cyst. 
The  contents  of  pancreatic  cysts  are  occasionally  viscid 
and  the  presence  of  mucin  has  been  demonstrated. 
Microscopic  examination  usually  shows  the  presence  of 
epithelial  cells,  globules  of  fat,  crystals  of  fatty  acids,  red 
blood-corpuscles,  leucocytes,  and  necrotic  tissue. 

It  is  often  possible  to  demonstrate  one  or  more  of  the 
three  well-known  enzymes  of  the  pancreatic  juice  in  the 
contents  of  pancreatic  cysts,  but  proteolytic,  lipolytic, 
and  diastatic  enzymes  have  been  found  in  fluid  removed 
from  abdominal  cysts  which  have  not  had  their  origin  in 
the  pancreas.  Korte  has  found  a  weak  diastatic  enzjnne 
in  a  mesenteric  cyst;  the  presence  of  pol>Tiuclear  leuco- 
cytes may  give  proteolytic  activity  to  any  fluid  which 
contains  them,  whereas  the  wide  distribution  of  fat- 
splitting  enzymes  is  well  known.  Moreover,  the  contents 
of  true  cysts  of  the  pancreas  may  exhibit  no  enzymotic 
activity;  the  anti-tryptic  action  of  blood-serum  may  ex- 


CYSTS  273 

plain  the  absence  of  trypsin  in  hemorrhagic  cysts  and 
Heidenhain  ^'^  has  shown  that  enzymes  disappear  in  the 
secretion  of  a  chronically  inflamed  gland.  Nevertheless, 
if  an  abdominal  cyst  contains  fluid  capable  of  digesting 
coagulated  egg  albumen  or  of  splitting  starch  its  origin 
in  the  pancreas  is  probable. 

Relation  of  Pancreatic  Cysts  to  Adjacent  Organs; 
Physical  Signs. — Cysts  of  the  pancreas  are  usually 
spherical  and  have  a  smooth  surface.  In  many  instances 
they  have  been  as  large  as  a  man's  head,  but  occasionally 
a  pancreatic  cyst  may  distend  the  abdominal  cavity  reach- 
ing from  ensiform  cartilage  to  symphysis  pubis.  Fluc- 
tuation can  usually  be  felt  when  the  tumor  is  grasped 
between  the  hands  but  occasionally  the  sac  is  so  tensely 
distended  that  it  appears  to  be  solid.  Korte  has  collected 
the  recorded  cases  of  pancreatic  cyst  and  has  defined 
the  positions  which  the  tumor  may  occupy.  The  tumor 
is  usually  situated  in  the  midline  between  ensiform  carti- 
lage and  umbilicus  (forty-eight  instances)  and  may  pro- 
duce a  rounded  protrusion  of  the  abdominal  wall ;  in  forty 
cases  the  greater  part  of  the  mass  has  lain  to  the  left  of 
the  midline,  whereas  in  only  ten  cases  has  the  greater 
part  been  on  the  right  side.  Large  or  unusually  movable 
cysts  have  extended  into  the  lower  part  of  the  abdominal 
cavity,  and  in  sixteen  cases  have  projected  below  the 
mnbilicus. 

Cysts  of  the  pancreas  usually  exhibit  little  mobility, 
but  when  in  contact  with  the  diaphragm  they  move  with 
respiration.  Cysts  of  the  tail  of  the  pancreas  may  be 
freely  movable ;  in  a  case  of  Lazarus  a  fluctuating  tumor 

"Heidenhain:  Pfliiger's  Arch.,  1875,  x,  557. 
18 


274 


DISEASE  OF  THE  PANCREAS 


the  size  of  a  child's  head  was  situated  in  the  left  liypo- 
chondrium  but  could  be  pushed  from  the  margin  of  the 
quadratus  lumborum  on  the  left  to  the  mamillary  line  on 
the  right.  Cysts  in  contact  with  the  aorta  may  transmit 
its  pulsation  but  cease  to  pulsate  when  the  patient  is  in 
the  knee-chest  position. 


Fig.  35. — A  cyst  projecting  from  the  ventral  surface  of  the  pancreas  into  the  bursa 
omentalis  (from  Oser,  Erkrankungen  des  Pankreas).  The  stomach  is  in  front  of  the  cyet 
and  with  its  growth  is  pushed  upward;  the  transverse  colon  is  below  it.  M,  stomach; 
C,  transverse  colon;  F,  pancreas;  M.t.,  transverse  mesocolon. 


The  relation  of  different  parts  of  the  pancreas  to 
adjacent  organs  determines  the  position  of  a  cyst  and  the 
physical  signs  which  it  presents.  Its  relation  to  the 
stomach  and  colon,  best  defined  after  artificial  distention 


CYSTS 


275 


of  these  organs,  is  important  for  diagnosis.  From  a 
study  of  one  hundred  and  thirty-three  cysts  with  opera- 
tion Korte  has  classified  the  positions  which  cysts  may 
occupy  as  follows: 


Liver  dulness 


Transverse 
colon 


Fig.  36. — The  relation  of  the  cyst  shown  in  Fig.  35  to  adjacent  organs.     (From  Korte,  Die 
chirurgischen  Krankheiten  des  Pankreas.) 


A  (Figs.  35  and  36). — Cysts  of  the  pancreas  usually 
project  from  the  anterior  surface  of  the  pancreas  into 
the  lesser  peritoneal  cavity ;  pushing  the  stomach  upward 
they  are  covered  by  the  gastrocolic  omentum.  Accumu- 
lation of  fluid  in  the  lesser  peritoneal  cavity  from  what- 


276 


DISEASE  OF  THE  PANCREAS 


ever  cause  closely  resembles  pancreatic  cyst  (Lloyd  ^*). 
Small  cysts  may  lie  behind  the  stomach  but  as  the  cyst 
increases  in  size  the  viscus  is  pushed  upward.  The  stom- 
ach when  distended  lies  above  the  tumor  and  its  tympany 
separates  the  dulness  of  the  tumor  from  that  of  the  liver ; 


L.h^. 


Fio.  37. — A  pancreatic  cyst  (IT)  which  has  pushed  its  way' between  Uver  (L)  and 
stomachKAf )  and  is  in  contact  with  the  lesser  omentum  (Ugamentum  hepatogastricum 
L.  h.  g.)  (from  Oser). 

the  colon  lies  below  the  tumor  and  may  be  pushed  down- 
ward to  the  symphysis  pubis. 

B  (Figs.  37  and  38). — In  a  few  instances  (in  nine  of 
the  cases  collected  by  Korte)  the  cyst,  arising  from  the 
upper  border  of  the  body  of  the  pancreas,  which  is  at  a 

"  Lloyd,  J. :  British  Med.  Jour.,  1892,  ii,  1051. 


CYSTS 


277 


higher  level  than  the  lesser  curvature  of  the  stomach  (see 
Chap.  I),  makes  its  way  between  the  stomach  and  the 
liver  and  is  covered  by  the  gastrohepatic  omentum.  Dul- 
ness  caused  by  the  tumor  is  in  contact  with  the  dulness  of 


Transverse 
colon 


Fig.  38. — A  pancreatic  cyst  (see  Fig.  37)  between  liver  and  stomach  (from  Korte). 

the  liver  and  the  stomach  is  at  the  lower  border  of  the 
cyst,  but  when  distended  may  cover  it  completely. 
Payr  ^®  has  described  a  case  in  which  the  cyst  passed 


Payr:  Wiener  klin.  Woeh.,  1898,  xii,  629. 


278 


DISEASE  OF  THE  PANCREAS 


through  the  foramen  of  Winslow  into  the  general  peri- 
toneal cavity. 

C. — The  cyst  may  grow  between  the  two  layers  of  the 
mesocolon.  Since  the  tail  of  the  pancreas  lies  between 
the  layers  of  the  mesocolon  cysts  of  this  i)art  of  the  gland 


Fig.  39. — A  pancreatic  cyst  (T)  which  has  penetrated  between  the  folds  of  the  tran.s- 
verse  mesocolon  (Af.  t.)  and  projects  upon  its  upper  surface.  The  .stomach  is  above  and 
the  transverse  colon  is  below  the  tumor  (from  Oser) . 

tend  to  push  their  way  into  the  membrane.  In  seven  of 
the  cases  collected  by  Korte  tlie  cyst  projected  upon  the 
upper  surface  of  the  mesocolon  (Fig,  39)  and  lay  between 
stomach  and  colon;  in  three  instances  the  cyst  projected 
upon  the  under  surface  of  the  mesocolon  (Figs.  41  and 
42)  and  both  stomach  and  colon  lay  above  it.     The  colon 


CYSTS 


279 


may  cross  the  summit  of  the  cyst  (Fig.  40)  and  the  layers 
of  the  mesocolon  are  equally  distended  (Petrykowski^^). 
Dreyzehner^i  has  described  a  case  in  which  the  cyst 
arising  from  the  head  of  the  pancreas  grew  to  the  right 
and  lay  behind  the  peritoneum,  displacing  the  right, 
kidney. 


...c 


Fig.  40. — A  pancreatic  cyst  (T)  which  has  penetrated  between  the  folds  of  the  trans- 
verse mesocolon  (M.<.)  and  projects  equally  upon  the  upper  and  lower  surface.  The 
stomach  is  above  the  cyst  and  the  transverse  colon  crosses  it  (from  Oser). 

Cysts  of  the  pancreas  may  rupture  into  fhe  peritoneal 
cavity  and  in  the  case  of  Schwartz  ^^  rupture  has  been 
the  result  of  injury  caused  by  a  fall.     Spontaneous  dis- 

^  Petrykowski :  Inaug.  Diss.,  Wurzburg,  1889. 
''Dreyzehner:  Arch.  f.  klin.  Chir.,  1895,  1,  261. 
^  Schwartz :  Sem.  med.,  1893,  xiii,  281. 


280 


DISEASE  OF  THE  PANCREAS 


appearance  of  the  tumor  without  evidence  of  intraperi- 
toneal rupture  has  occurred  in  association  with  temporary 
diarrhoea  and  has  suggested  that  the  contents  have  en- 
tered the  intestine.  In  the  case  of  BulP^  dark  masses 
were  passed  in  the  stools,  whereas  in  a  case  of  Parsons  ^* 


Fig.  41. — A  pancreatic  cjoL  {T)  wliich  has  penetrated  between  the  folds  of  the  trans- 
verse mesocolon  and  projects  upon  its  lower  surface.  Both  stomach  and  transverse  colon 
are  above  the  cyst  (from  Oser). 

there  was  profuse  whitish  diarrhceal  discharge.  Disap- 
pearance of  an  epigastric  cyst  described  by  Payr  occurred 
three  times  during  two  months  and  was  followed  each 
time  by  diarrhoea.     It  is  probable  that  discharge  of  con- 

"Bull:  New  York  Med.  Jour.,  1887,  xlvi,  376. 
^  Parsons :  British  Med.  Jour.,  1857,  i,  475. 


CYSTS  281 


tents  may  occur  through  pancreatic  ducts  communicating 
with  the  cyst. 

Symptoms. — Pain  is  almost  always  present  and  may 
be  caused  by  a  cyst  which  is  not  palpable.     It  varies  in 


Stomach 


Transverse 
colon 

Cyst,  absolute 
dulness 


Cyst,  relative 
dulness 


Fig.  42. — A  pancreatic  cyst  which  projects  from  the  under  surface   of  the   mesocolon 
(see  Fig.  41)  (from  Korte). 

intensity  and  location  and  may  occur  in  paroxysms;  it 
has  little  value  for  diagnosis.  Pressure  by  the  cyst  upon 
the  stomach,  particularly  when  the  organ  is  bound  to  the 
cyst  by  adhesions,  may  cause  gastric  disturbance  asso- 


282  DISEASE  OF  THE  PANCREAS 

dated  perhaps  with  vomiting.  Colicky  pain,  constipa- 
tion, or  in  rare  instances  intestinal  obstruction,  have  been 
caused  by  pancreatic  cysts  which  compress  the  intestine 
and  occlude  its  lumen. 

Jaundice  is  less  common  with  cyst  than  with  car- 
cinoma, because  the  lesion  less  frequently  occupies  the 
head  of  the  gland.  Other  symptoms  which  occasionally 
occur  as  the  result  of  pressure  upon  adjacent  organs  are 
dilatation  of  superficial  branches  of  the  portal  vein, 
ascites,  due  to  pressure  upon  the  portal  vein,  and  oedema 
of  the  lower  extremities,  due  to  pressure  upon  the  inferior 
vena  cava.  In  two  instances  the  right  ureter  (Dreyzeh- 
ner.  Reeve-'')  has  been  obstructed.  -Dyspnoea  results 
from  direct  pressure  upon  the  diaphragm  or  from  disten- 
tion of  the  abdominal  cavity. 

Disturbances  of  digestion  referable  to  diminution  of 
pancreatic  juice  in  the  intestine  occur  in  a  small  number 
of  cases.  Fitz,^^  reviewing  the  literature  of  the  subject, 
found  only  two  instances  (Bull,  Goodman)  of  steator- 
rhcea  with  cyst,  and  in  only  two  cases  was  disturbed  diges- 
tion of  protein  indicated  by  the  presence  of  undigested 
muscle-fibres  in  the  faeces.  Such  disturbances  of  diges- 
tion indicate  advanced  destruction  of  the  gland,  and  in 
all  of  the  cases  just  cited  in  which  they  have  occurred 
glycosuria  has  been  present. 

Glycosuria  and  diabetes  mellitus  follow  chronic  in- 
flammation  caused   l)y   tlie   presence   of   a   cyst  which, 
occludes  the  ducts  of  the  gland.     Diabetes  occurred  in 
only  nine  of  one  hundred  and  thirty-four  cases  collected 


Reeve:  Ann.  of  Surg.,  1893,  xviii,  227. 
'Fitz:    hoc.  cH.,  p.   00. 


CYSTS  283 

by  Oser.  In  a  case  of  Lazarus  there  was  alimentary 
glycosuria. 

Emaciation,  which  is  a  frequent  symptom  of  pancre- 
atic C3''st,  cannot  be  satisfactorily  explained  by  disturb- 
ance of  pancreatic  digestion.  Rapid  gain  of  weight  may 
follow  removal  of  the  cystic  contents  and  drainage.  Laz- 
arus noted  the  loss  of  eighteen  kilogrammes  of  body 
weight  during  three  months  in  a  young  man  with  pan- 
creatic cyst  following  abdominal  injury.  Recovery 
quickly  followed  operation  and  fifteen  pounds  was  re- 
gained within  six  weeks.  In  another  patient  of  Lazarus 
twenty-eight  kilogrammes  of  body  weight  were  lost 
within  a  year  after  the  appearance  of  a  pancreatic  cyst. 

A  cyst  may  have  been  recognizable  by  the  patient 
years  before  it  is  seen  by  the  surgeon  and  its  increase  in 
size  is  often  slow.  In  a  case  described  by  Hulke  ^^  a  cyst 
in  a  woman  forty-seven  years  of  age  had  existed  since 
childhood.  Cystadenomata  develop  slowly  but  sudden  in- 
crease in  size  may  occur.  With  pseudocysts  rapid  en- 
largement is  not  infrequent.  Traumatic  cysts  usually 
appear  within  a  few  weeks  after  injury. 

Diagnosis. — ^A  fluctuating  spherical  tumor  in  the  epi- 
gastric region,  particularly  when  it  is  situated  in  great 
part  to  the  left  of  the  median  line,  suggests  pancreatic 
cyst.  The  cyst  usually  reaches  the  abdominal  wall  be- 
tween the  stomach,  which  partially  covers  it,  and  the 
transverse  colon;  the  greatest  difficulty  in  diagnosis  is 
with  those  uncommon  cysts  which  find  their  way  above 
the  stomach  and  are  in  contact  with  the  liver. 

Percussion  while  the  stomach  is  undergoing  inflation 

="  Hulke :  Lancet,  1892,  ii,  1273. 


284  DISEASE  OF  THE  PANCREAS 

is  often  useful,  for  it  shows  that  the  lower,  or  less  fre- 
quently the  upper,  border  of  the  tumor  mass  is  gradually 
covered  as  the  organ  increases  in  size.  A  cyst  of  the 
liver,  the  distended  gall-bladder,  or  a  cyst  of  the  spleen 
on  the  contrary  remains  superficial,  for  they  are  not 
pushed  backward  and  covered  by  the  distended  stomach. 

Cysts  of  the  mesentery  are  usually  found  near  the 
umbilicus  and  are  freely  movable  in  all  directions.  Cysts 
of  the  pancreas  situated  in  the  mesocolon  as  well  as  cysts 
of  great  size  may  descend  as  far  as  the  pelvis,  and  in  some 
instances  have  been  mistaken  for  ovarian  cysts.  A  his- 
tory of  origin  in  the  epigastric  region  may  indicate 
pancreatic  cyst;  location  behind  the  stomach  and  colon, 
best  shown  after  distention  of  these  organs,  and  the  ab- 
sence of  any  connection  with  the  uterus  or  ovaries  demon- 
strable by  bimanual  examination  of  vagina  and  rectum, 
may  exclude  ovarian  cyst.  Disappearance  of  the  pan- 
creatic tumor  may  suggest  hydronephrosis;  pulsation 
transmitted  from  the  aorta  has  suggested  the  presence 
of  aneurism  of  the  aorta. 

Treatment. — Cysts  of  the  pancreas  have  been  more 
successfully  treated  by  surgical  methods  than  other  les- 
ions of  the  gland.  The  greater  number  of  pancreatic 
cysts  have  no  epithelial  lining  and  tend  to  disappear 
after  incision  and  drainage — a  method  first  used  by  Gus- 
senbauer  ^^  in  1883.  Of  one  hundred  and  two  cases  with 
operation  collected  by  Korte  one  hundred  and  one  have 
been  treated  by  this  method  and  only  four  have  died  as 
the  result  of  the  operation.  Wlien  the  cyst  occupies  the 
epigastrium  or  right  hypochondrium  it  is  usually  reached 
with  most  convenience  by  incision  through  the  abdominal 

"  Gussenbauer :  Langenbeck's  Arch,  f .  Chir.,  1883,  xxix,  355. 


CYSTS  285 

wall.  In  some  instances  the  cyst  has  been  exposed  and 
united  to  the  abdominal  wall  and  several  days  later 
opened.  Incision  through  the  lumbar  region,  which  may 
be  possible,  especially  when  the  cyst  occupies  the  left 
side  of  the  abdomen,  does  not  open  the  peritoneal  cavity 
and  may  afford  efficient  drainage.  The  cavity  of  the  cyst 
is  packed  with  gauze  to  secure  drainage  and  the  wound, 
frequently  complicated  by  pancreatic  fistula,  heals  slowly. 

Attempts  have  been  made  to  treat  pancreatic  cysts 
by  aspiration  of  the  contents  but  the  method  has  proved 
ineffectual  and  dangerous.  The  operation  has  caused 
rupture  of  a  cyst.  General  peritonitis  has  occurred  when 
the  cyst  has  been  the  site  of  pyogenic  infection,  or  hemor- 
rhage has  followed  puncture  of  the  much  enlarged  blood- 
vessels which  occupy  the  wall  of  many  cysts. 

After  aspiration  the  contents  of  the  cyst  almost  con- 
stantly reaccumulate.  Israel  '^^  described  a  case  in  which 
recovery  followed  aspiration.  In  this  instance  laparot- 
omy exposed  a  cyst  covered  by  the  stomach  which  was 
attached  to  the  tumor  by  firm  adhesions;  the  cyst  was 
punctured  through  the  stomach  and  a  litre  of  brown  fluid 
was  aspirated;  the  cyst  did  not  reappear. 

Complete  extirpation  of  a  pancreatic  cyst,  first  per- 
formed by  Bozeman^*^  in  1882,  is  rarely  possible.  The 
proximity  of  large  blood-vessels  and  other  important 
structures,  the  presence  of  adhesions  and  the  danger  of 
diabetes  mellitus  after  removal  of  a  large  part  of  the  pan- 
creas, make  the  operation  in  most  cases  impracticable. 
Extirpation  is  performed  with  least  difficulty  when  the 
cyst  occupies  the  tail  of  the  gland  and  has  a  well-defined 

"*  Israel :  Deutsche  klin.  Woch.,  1900,  xxvi,  352. 
'°  Bozeman :  New  York  Med.  Rec,  1882,  xxi,  46. 


286  DISEASE  OF  THE  PANCREAS 

wall.  It  offers  the  greatest  chance  for  permanent  recov- 
ery when  the  presence  of  mnltilocular  cysts  or  papillary 
growths  suggest  cystadenoma ;  pancreatic  fistula,  com- 
monly present  after  incision  and  drainage,  is  usually 
avoided  when  complete  extirpation  of  the  cyst  is  accom- 
plished. In  some  cases  attempted  extirpation  has  been 
abandoned  because  adhesions  or  other  complications  have 
rendered  the  operation  impossible ;  in  such  cases  the  cyst 
has  been  partially  removed.  Mayo  Robson  ^^  found  rec- 
ords of  one  hundred  and  sixty  cases  in  which  cyst  had 
been  treated  by  operation ;  in  twenty  instances  death  fol- 
lowed operation  and  in  eight  instances  death  occurred 
subsequently  as  the  result  of  diabetes  or  other  complica- 
tion. Among  one  hundred  and  thirty-eight  cases  treated 
by  incision  and  drainage  death  occurred  in  sixteen; 
among  fifteen  cases  with  complete  excision  death  occurred 
in  three;  among  seven  cases  with  partial  excision  deatli 
occurred  in  one. 

Zweifel  ^^  removed  a  cyst  and  all  of  the  pancreas  save 
a  part  of  the  head  3  cm.  in  length;  glycosuria,  found  ten 
days  later,  persisted  twelve  days,  but  had  disappeared 
at  the  end  of  two  months. 

Pancreatic  fistula  usually  follows  incision  and  drain- 
age or  partial  removal  of  pancreatic  cysts  and  occasion- 
ally occurs  after  complete  extirpation.  Such  fistulce  may 
close  after  a  short  time,  l)nt  in  some  instances  they  have 
persisted  a  year  or  more;  a  fistula  described  by  Korte 
persisted  two  and  a  half  years.  In  a  case  of  Murray  ^^ 
fistula  had  not  healed  after  three  years.     There  may  be 

"  Mayo  Robson :  Lancet,  1904,  i,  773. 

"  Zweifel :  Cent,  f .  Gynaee.,  1894,  xviii,  641. 

'"Murray  and  Gies:  American  Med.,  1902,  iv,  133. 


CYSTS  287 

active  secretion  of  pancreatic  juice  in  which  pancreatic 
enzymes  are  readily  demonstrable ;  Gushing  "^  records  the 
discharge  of  from  500  to  600  c.c.  of  fluid  daily.  Gies  ^^ 
studying  the  secretion  from  the  fistula  observed  by  Mur- 
ray found  from  0.46  to  0.93  per  cent,  of  solids  and  no  evi- 
dence of  the  presence  of  enzymes  derived  from  the 
pancreas. 

The  secretion  may  irritate  and  erode  the  skin  about 
the  wound  unless  the  surface  is  kept  clean  by  careful 
dressing. 

Attempts  have  been  made  to  hasten  the  healing  of  such 
fistulas  by  injection  of  tincture  of  iodine,  silver  nitrate, 
chloride  of  zinc,  and  other  substances,  and  the  sinus  has 
been  scraped  or  cauterized.  Lazarus  describes  a  case  in 
which  injection  of  silver  nitrate  was  followed  by  collapse 
and  death,  probably  caused  by  hemorrhagic  necrosis  of 
the  pancreas  referable  to  the  irritant.  Hemorrhage  from 
the  tract  may  occur  and  has  occasionally  followed  curet- 
ting. In  some  instances  the  tract  has  been  excised;  in 
other  cases  an  excision  has  been  made  into  the  sinus 
from  the  back  and  after  better  drainage  has  been  secured 
its  closure  has  been  hastened.  Conditions  which  dimin- 
ish the  flow  of  pancreatic  juice  are  believed  to  favor  the 
disappearance  of  fistul^e  (see  page  78).  "Wohlgemuth'^ 
has  recommended  that  the  patient  be  put  upon  a  diabetic 
diet  and  be  given  small  doses  of  sodium  carbonate ;  favor- 
able results  have  been  recorded  (Heineke,^^  Karewski^'). 

"  Gushing,  H.  W. :  Boston  Med.  and  Surg.  .Jour.,  1898,  exxxviii, 
429. 

""  Wohlgemuth :  Berliner  klin.  Woeh.,  1907,  sliv,  47. 

'"Heineke:  Cent.  f.  Chir.,  1907,  xxxiv,  265. 

"  Karewski :  Berliner  klin.  Woeh.,  1907,  xliv,  187. 


CHAPTER  XIII. 


CARCINOMA. 


The  incidence  of  malignant  growth  of  the  pancreas  is 
shown  by  the  statistics  of  Segre,^  among  11,472  autopsies 
carcinoma  occurred  127  times,  and  sarcoma  twice.  Be- 
nign tumors,  including  the  so-called  proliferation  cysts, 
are  even  less  common.  Primary  carcinoma  occurs  more 
frequently  in  men  than  in  women ;  of  106  cases  collected 
by  Miraillie,2  69  were  in  men  and  37  in  women. 

The  head  of  the  gland  is  the  common  site  of  the  tumor ; 
among  57  cases  collected  by  Segre  the  entire  gland  was 
affected  in  19  instances,  whereas  the  tumor  occupied  the 
head  of  the  gland  in  35  instances,  the  body  twice,  and  the 
tail  once.  The  head  of  the  pancreas  was  the  ••seat  of 
prunary  carcinoma  in  82  among  113  cases  of  Miraillie. 

Carcinoma  of  the  pancreas  is  usually  of  the  scirrhus 
type  and  is  composed  of  firm  fibrous  nodules,  but  occa- 
sionally it  is  encephaloid,  soft  and  cellular.  Colloid  car- 
cinoma of  the  pancreas  has  been  observed.  Cystic  epithe- 
lioma is  described  by  Roux  ^  and  a  malignant  papillary 
adenocystoma  described  by  Sotti  *  formed  metastases 
in  lymphatic  glands  and  lungs,  and  papillary  metastases 
by  implantation  upon  the  surface  of  the  peritoneum. 
Carcinomatous  tumors  of  the  pancreas  are  usually  small 
(5  to  10  cm.  across),  but  occasionally  they  attain  con- 

*  Segre :  Annal.  univ.  di  med.  e  chir,,  1888.     Quoted  by  Oser. 

*  Miraillie :  Gaz.  des  hop.,  1893,  Ixvi,  889. 

'  Roux :    Cancer  et  kystes  du  pankreas.     Paris,  1891. 

*  hoc.  eit. 
288 


CARCINOMA  289 

siderable  size.  Wlien  a  large  tumor  invades  adjacent 
organs — namely,  the  liver,  bile  passages,  stomach  and 
duodenum — its  origin  may  be  doubtful.  Metastases  from 
pancreatic  tumors  occur  with  greatest  frequency  in  the 
liver. 

When  the  tumor  comes  into  contact  with  adjacent 
organs  adhesions  are  formed,  and  a  variety  of  lesions 
are  the  result  of  pressure.  Occlusion  of  the  duodenum 
or  pylorus  may  cause  dilatation  of  the  stomach;  the 
stomach  may  be  compressed  against  the  abdominal  wall 
and  compression  of  the  transverse  colon  may  cause  intes- 
tinal obstruction.  Obstruction  of  the  bile  duct  with 
jaundice  is  common.  Pressure  upon  the  left  ureter  may 
cause  hydronephrosis ;  pressure  upon  the  portal  vein  may 
cause  ascites ;  pressure  upon  the  inferior  vena  cava  may 
be  followed  by  oedema  of  the  lower  extremities.  Ne- 
crosis with  ulceration  of  tumor-tissue  invading  the  stom- 
ach or  duodenum  may  cause  perforation  of  these  organs. 

Metastatic  nodules  from  tumors  primary  in  other 
organs  occur  in  the  pancreas.  Secondary  invasion  of  the 
pancreas  by  tumors  of  surrounding  organs,  particularly 
of  the  stomach,  is  common. 

Fahndrieh  °  has  claimed  that  tumors  apparently  primary  in  the 
gland  are  often  derived  from  the  mucosa  of  the  stomach.  Olivier' 
examined  an  adenocarcinoma  of  the  head  of  the  pancreas  and  obtained 
evidence  that  it  had  its  origin  in  Brunner's  glands  of  the  duodenum. 
He  thinks  that  careful  microscopic  examination  is  necessary  in  order  to 
determine  the  primary  site  of  tumors  in  this  situation. 

The  origin  of  carcinoma  in  various  histological  elements  of  the 
gland  has  been  much  discussed.     Adenocarcinoma  composed  of  cylin- 

" Fahndrieh:    Inaug.  Diss.,  1891. 
•Olivier:  Ziegier's  Beitrage,  1894,  xv,  351. 
19 


290  DISEASE  OF  THE  PANCREAS 

drical  cells  arranged  in  irregular  alveoli  with  a  central  lumen  are 
derived,  according  to  Hulst,'  from  the  ducts  of  the  gland,  whereas  the 
less  common  tumors  composed  of  polygonal  cells  packed  together  to 
form  solid  alveoli  are  probably  derived  from  the  secreting  cells  of  the 
acini.  Olivier,  on  the  contrary,  has  shown  that  solid  alveoli  may  be 
continuous  with  ducts  of  the  gland.  Hulst  has  found  no  relation  be- 
tween such  tumors  and  the  islands  of  Langerhans,  but  Tabozzi  *  from 
a  study  of  five  cases  has  fonned  the  opinion  that  carcinoma  solidum  has 
its  origin  in  the  islands  of  Langerhans. 

Cystic  adenomata  have  been  described  (p.  268). 
Solid  adenomata  of  small  size  have  occasionally  been  dis- 
covered at  autopsy.  Biondi  ^  described  an  encapsulated 
fibroadenoma  of  the  head  of  the  pancreas  which  was 
palpable  and  caused  jaundice ;  recovery  followed  removal, 
and  there  was  no  recurrence  a  year  and  a  half  later. 

A  tawny  yellow  tumor  the  size  of  a  large  pea  has  been 
described  by  Nichols.^"  It  had  the  histological  structure 
of  an  island  of  Langerhans.  Helmoltz  "  has  described 
a  small  tumor  of  the  same  kind.  A  similar  body  resem- 
bling a  greatly  hypertrophied  island  of  Langerhans  has 
been  found  by  Cecil. ^^ 

Sarcoma  of  the  pancreas  rarely  occurs,  and  Kakels  ^^ 
in  1902  was  able  to  collect  only  twenty-one  instances, 
among  which  only  ten  were  certainly  primary;  three  of 
these  primary  growths  were  in  the  tail  of  the  gland. 
Fibrosarcoma  and  medullary  sarcoma  have  been  found; 


'  Hulst :  Virchow's  Arch.,  1905,  clxxx,  288. 
^Fabozzi:  Ziegler's  Beitriige,  1903,  xxxiv,  199. 
"Biondi:    Riforma  med.,  1896,  ii,  97. 
"Nichols:  Jour,  of  Med.  Res.,  1902,  viii,  385. 
"  Helmoltz :  Bull,  of  the  Johns  Hopkins  Hosp.,  1907,  xviii,  185. 
'"  Loe.  cit. 
"Kakels:    American  Jour,  of  the  Med.  Scien.,  1902,  cxxiii,  471. 


CARCINOMA  291 

lymphosarcoma  and  angiosarcoma  are  described.  The 
age  of  the  affected  individuals,  ranging  from  four  to 
seventy  years,  is  not  significant  for  diagnosis.  Mal- 
colm ^^  removed  a  sarcomatous  tumor  (not  included  in  the 
series  just  mentioned)  from  the  tail  of  the  pancreas  of 
a  child  four  years  old;  the  tumor  was  five  inches  across, 
and  had  invaded  the  portal  vein. 

Chronic  inflammation  occurs  in  the  immediate  neigh- 
borhood of  carcinoma  which  is  invading  and  replacing 
the  pancreatic  parenchyma.  The  tumor-mass,  which  is 
usually  situated  in  the  head  of  the  gland,  compresses, 
when  of  sufficient  size,  the  pancreatic  duct,  and  causes 
chronic  interlobular  pancreatitis  of  that  part  of  the  gland 
which  is  distal  to  the  obstruction.  In  Chapter  IX  it  has 
been  shown  that  the  islands  of  Langerhans  are  spared 
for  a  time  by  the  inflammatory  process  which  follows 
occlusion  of  the  ducts,  even  though  the  secreting  paren- 
clnnna  is  destroyed.  Pearce  ^^  found  that  the  islands 
of  Langerhans  persist  at  the  edge  of  the  advancing  new 
growth  and,  at  times  hyper trophied,  are  surrounded  by 
dense  stroma  which  contains  no  secreting  acini.  The 
islands  of  Langerhans  are  finally  destroyed,  and  in  one 
of  the  cases  of  Pearce  carcinoma  with  diabetes  mellitus 
was  associated  with  advanced  sclerosis  implicating  these 
islands,  whereas  in  a  second  case  with  temporary  glyco- 
suria the  tumor  affected  only  the  head  of  the  pancreas. 

Symptoms. — Pain  is  one  of  the  earliest  symptoms  of 
pancreatic  cancer  and  is  almost  constantly  present.  Its 
great  intensity  increasing  until  death,  according  to  some 

"  Malcolm :  Lancet,  1902,  i,  586. 

''  Pearce :  American  Jour,  of  the  Med.  Scien.,  1904,  exxviii,  478. 


292  DISEASE  OF  THE  PANCREAS 

writers,  is  referable  to  pressure  upon  the  coeliac  ganglion 
or  adjacent  nerve-trunks.  Pain  is  usually  localized  in 
the  epigastric  region  and  may  radiate  to  the  back  or 
shoulders.  It  has  been  suggested  that  colicky  pain  may 
be  caused  by  occlusion  of  the  pancreatic  duct  and  may 
resemble  the  colic  of  pancreatic  lithiasis;  in  some  cases 
it  is  doubtless  caused  by  pressure  upon  the  common  bile 
duct  and  resembles  biliary  colic. 

In  only  a  fourth  or  a  fifth  of  the  cases  of  primary 
cancer  of  the  pancreas  collected  by  Miraillie  has  a  tumor- 
mass  been  palpable.  Abundant  fat,  muscular  abdominal 
walls  or  tenderness  on  pressure  may  prevent  the  recog- 
nition of  a  mass.  The  tumor  is  usually  situated  in  the 
epigastric  region,  but  occurs  rarely  in  the  right  or  left 
hypochondrium.  It  is  deep-seated,  in  most  instances 
ill-defined,  and  on  palpation  appears  smaller  than  it  is  in 
reality.  It  is  usually  immovable,  but  occasionally  moves 
with  respiration  or  transmits  the  pulsation  of  the  aorta. 

Metastatic  nodules  in  the  liver  secondary  to  cancer 
of  the  pancreas,  according  to  Bard  and  Pic,  are  small 
and  do  not  cause  the  great  enlargement  of  the  liver  which 
occurs  with  metastases  from  tumors  of  the  stomach  and 
intestine.  Nevertheless,  Miraillie  found  the  liver  en- 
larged in  seventeen  of  one  hundred  and  thirteen  cases 
of  pancreatic  cancer.  The  condition  of  the  liver  varies, 
and  in  some  cases  metastatic  nodules  have  been  large. 

Cachexia  occurs  with  pancreatic  cancer,  as  with  malig- 
nant growths  in  other  organs,  but  its  progress,  it  is 
claimed,  is  unusually  rapid  when  the  gland  is  the  seat  of 
the  disease.  Disturbances  of  pancreatic  digestion,  jaun- 
dice, and  diabetes  may  have  a  part  in  producing  extreme 
emaciation. 


CARCINOMA  298 

Symptoms  of  gastric  or  of  gastro-intestinal  disturb- 
ance  often  occur  before  other  symptoms;  there  may  be 
loss  of  appetite,  discomfort  after  eating,  nausea  and 
vomiting.  Distaste  for  meat  has  been  mentioned  as  a 
symptom  of  the  disease.  Constipation  occurs  more  fre- 
quently than  diarrhoea,  but  in  some  cases  neither  is 
present. 

SjTnptoms  due  to  disturbance  of  pancreatic  function 
are  present  in  a  small  proportion  of  instances  of  primary 
cancer.  Fatty  stools  occurred  in  nine  of  one  hundred 
and  thirteen  cases  of  Miraillie ;  Fitz  ^^  found  in  the  litera- 
ture of  the  subject  only  eleven  cases  with  steatorrhoea, 
whereas  evidence  of  disturbed  digestion  of  protein — 
undigested  muscle-fibres  in  the  faeces — has  been  recorded 
in  two  instances.  Bulky  stools  due  to  disturbed  pan- 
creatic digestion,  according  to  Oser,  may  be  a  symptom 
of  pancreatic  carcinoma. 

Diabetes  mellitus  not  infrequently  occurs  as  the  re- 
sult of  destruction  of  the  pancreas,  caused  by  cancer; 
alimentary  glycosuria  without  symptoms  of  diabetes  has 
been  observed.  In  thirteen  of  fifty  cases  cited  by  Mirail- 
lie there  was  sugar  in  the  urine;  eight  additional  cases 
with  diabetes  mellitus  and  two  with  alimentary  glycosuria 
cited  by  Oser.  The  studies  of  Pearce,  who  has  de- 
scribed two  cases  with  permanent  and  one  with  alimen- 
tary glycosuria,  show  the  relationship  of  cancer  to  the 
islands  of  Langerhans  and  to  disturbance  of  carbohy- 
drate metabolism.  The  persistence  of  islands  of  Lan- 
gerhans embedded  in  carcinomatous  tissue  explains  the 
absence  of  glycosuria  even  though  the  entire  pancreas 

^^Loc.  cit.,  p.  90. 


294  DISEASE  OF  THE  PANCREAS 

has  been  apparently  replaced  by  new  growth.  Their 
ultimate  destruction  explains  its  onset.  Glycosuria  with 
cancer,  as  with  other  conditions  which  cause  cachexia, 
may  disappear  before  death  (Courmont  and  Bret^^). 

Symptoms  referable  to  pressure  of  the  new  growth 
upon  adjacent  organs  vary  with  its  location;  those  of 
greatest  frequency  are  caused  by  tumors  situated  in  the 
head  of  the  gland.  Jaundice  is  a  common  and  often  early 
symptom;  in  eighty-two  of  one  hundred  and  thirteen 
cases  of  carcinoma  of  the  pancreas  jaundice  has  been 
present.  Carcinoma  of  the  pancreas,  moreover,  is  one 
of  the  most  frequent  causes  of  obstruction  of  the  com- 
mon bile  duct  not  referable  to  cholelithiasis,  and  has 
occurred  in  fifty-four  of  one  hundred  and  thirty-nine 
cases  of  obstruction  (not  due  to  calculi)  collected  by 
Ecklin.^^  Jaundice  caused  by  tumor  exhibits  no  remis- 
sions, but  usually  increases  in  intensity  until  death  (black 
jaundice). 

Enlargement  of  the  gall-bladder  following  obstruc- 
tion of  the  common  bile  duct  by  carcinoma  has  been 
described  by  Battersby,^^  Bard  and  Pic,  and  others. 
Courvoisier  ^^  has  found  that  the  gall-bladder  is  usually 
contracted  when  obstruction  of  the  common  bile  duct  is 
due  to  biliary  calculi,  whereas  with  occlusion  from  other 
cause  the  gall-bladder  is  in  most  instances  dilated.  The 
gall-bladder  may  be  so  dilated  that  it  is  palpable  below 
the  ribs  on  the  right  side. 

"  Courmont  and  Bret :    Clinique,  1894,  viii,  621. 
"Ecklin:  Inaut,^  Diss.,  Basel,  l.Snfl. 

"Battersby:  Dublin  Jour,  of  the  Med.  Soien.,  1844,  xxv,  219. 
^°  Courvoisier :   Die  casuistiseh-statistischen  Beitrage  zur  Pathologic 
und  ChirurLne  der  Gallenwege,  Leipzis!:,  1890. 


CARCINOMA  295 

Ecklin  has  collected  one  hundred  and  seventy-two  instances  of 
obstruction  caused  by  gall-stones;  the  gall-bladder  has  been  contracted, 
usually  by  chronic  inflammation,  one  hundred  and  ten  times,  normal 
thirty-four  times,  and  dilated  twenty-eight  times.  Among  one  hundred 
and  thirty-nine  instances  in  whicli  tlie  dnct  lias  been  obstructed  by  other 
lesions,  the  gall-bladder  has  been  contracted  in  nine,  normal  in  nine, 
and  dilated  in  one  hundred  and  twenty-one  instances;  in  sixty-two  of 
these  one  hundred  and  thirty-nine  cases  obstruction  has  been  caused  by 
carcinoma  of  the  pancreas  and  among  these  eases  the  gall-bladder  has 
been  dilated  fifty-eight  times.  Dilatation  occurs  because  inflammatory 
changes  are  usually  absent. 

Pressure  upon  the  pylorus  or  duodenum  may  cause 
dilatation  of  the  stomach.  Intestinal  obstruction  due 
to  compression  of  the  ileum  has  been  observed.  Pres- 
sure upon  the  portal  vein  may  cause  ascites,  swelling  of 
the  spleen,  and  hemorrhoids.  Chylous  ascites  due  per- 
haps to  rupture  of  the  thoracic  duct  has  been  found. 

Diagnosis. — For  recognition  of  cancer  of  the  head  of 
the  pancreas  the  most  significant  symptoms  are  increas- 
ing jaundice  attaining  great  intensity,  dilatation  of  the 
gall-bladder  and  epigastric  tumor ;  rapid  emaciation  and 
advanced  age  may  suggest  malignant  disease.  The  pres- 
ence of  glycosuria,  or  rarely  of  steatorrhcea,  may  give 
evidence  of  pancreatic  disease.  Without  jaundice  or 
tumor  diagnosis  will  be  doubtful;  examination  under 
anaesthesia  after  the  stomach  and  colon  have  been  emptied 
increases  the  opportunity  for  palpation  of  a  tumor. 

With  cholelithiasis  onset  of  jaundice  is  more  sudden 
and  remissions  often  occur;  but  impacted  calculi  may 
cause  intense  jaundice.  A  palpable  gall-bladder  sug- 
gests cancer  rather  than  gall-stones,  but  a  thick  abdom- 
inal wall  may  prevent  the  recognition  of  an  enlarged 
gall-bladder.    With  cancer  there  are  usually  intense  pain. 


296  DISEASE  OF  THE  PANCREAS 

emaciation,  and  normal  or  subnormal  temperature, 
whereas  cholelithiasis  is  often  accompanied  by  fever. 

According  to  the  well-known  observations  of  Bard 
and  Pic  the  liver  is  not  enlarged,  whereas  with  hepatic 
cancer  having  its  primary  seat  in  organs  other  than  the 
pancreas  enlargement  is  usual;  nevertheless,  subsequent 
observations  have  shown  that  enlargement  of  the  liver 
may  occur. 

The  pancreatic  tumor  is  usually  less  movable  than 
tumors  of  the  pylorus  and  of  the  colon  and  its  position 
does  not  change  with  distention  of  these  organs. 

Carcinoma  of  the  tail  of  the  pancreas  may  be  mis- 
taken for  malignant  growth  at  the  cardiac  end  of  the 
stomach  or  in  the  wall  of  the  colon.  Takayasu  ^^  de- 
scribed an  immovable  tumor  felt  behind  the  left  rectus 
muscle;  inflation  of  the  stomach,  which  was  above  it, 
caused  its  partial  disappearance,  and  inflation  of  the 
colon  at  its  lower  margin  caused  complete  disappearance. 
Carcinoma  of  the  tail  of  the  pancreas  was  found  at 
operation. 

Treatment. — Pain,  jaundice,  diabetes  mellitiis,  or 
gastro-intestinal  symptoms  caused  by  cancer  of  the  pan- 
creas require  appropriate  medicinal  treatment.  Obser- 
vations upon  man  (Fles)  and  experiments  upon  animals 
(see  Chap.  IV)  indicate  that  the  disturbances  of  diges- 
tion which  are  caused  by  absence  of  pancreatic  juice  in 
the  intestine  may  be  favorably  influenced  by  administra- 
tion of  an  emulsion  prepared  from  the  fresh  pancreas  of 
an  animal,  or  by  use  of  pancreatin  (Oser),  which  contains 
both  trypsin  and  steapsin. 

"  Takayasu :  Mitt.  a.  d.  Grenzgeb.  d.  Med.  u.  Chir.,  1898,  iii,  89. 


CARCINOMA  297 

Tumors  of  the  pancreas  have  been  removed  by  opera- 
tion, and  in  approximately  one-half  of  such  cases  the 
patient  has  recovered  from  the  immediate  effects  of  the 
operation;  but  after  removal  of  a  malignant  growth 
death  has  usually  occurred  within  a  few  months.  Fifteen 
cases  have  been  collected  by  Villar  ^^  (1906) ;  in  seven  in- 
stances the  patient  recovered  from  the  operation,  and  in 
eight  death  followed  immediately.  Biondi^^  removed 
what  proved  to  be  a  fibro-adenoma  occupying  two-thirds 
of  the  head  of  the  pancreas ;  the  tumor  which  had  caused 
jaundice  was  palpable  before  operation  midway  between 
ensiform  cartilage  and  umbilicus,  and  was  apparently 
the  size  of  a  hen's  egg.  Recovery  followed,  and  the  pa- 
tient was  well  a  year  and  a  half  after  operation. 

Korte  collected  ten  cases  in  which  solid  tumors  were 
removed  from  the  pancreas,  and  in  six  the  mass  occupied 
the  tail  of  the  gland.  In  three  instances  sarcoma  of  the 
pancreas  was  removed.  Extirpation  of  tumors  situated 
in  the  head  of  the  pancreas  is  difficult  and  dangerous. 
Only  part  of  the  head  of  the  gland  can  be  removed,  for 
obliteration  of  the  ducts  is  followed  by  chronic  inflam- 
mation of  the  parenchyma  distal  to  the  point  of  oblitera- 
tion, and  advanced  sclerosis  following  occlusion  of  the 
pancreatic  ducts  is  accompanied  by  fatal  diabetes. 
Franke  ^*  believed  that  he  had  removed  the  entire  pan- 
creas containing  carcinoma;  there  was  glycosuria  from 
the  fifth  to  the  nineteenth  day  after  operation,  and  death 
occurred  at  the  end  of  five  months.  Complete  absence 
of  the  gland  was  not  confirmed  by  autopsy.    In  the  case 

^  Villar :  Chirurgie  du  pancreas.     Paris,  1906. 

^*  Biondi :  Cliniea  chirurgica,  1896,  No.  4.     Quoted  by  Korte. 

"  Franke :  Arch,  f .  klin.  Chir.,  1901,  xliv,  364. 


298  DISEASE  OF  THE  PANCREAS 

examined  by  Dr.  Marine  (see  Chap.  IV)  glycosuria  ap- 
peared immediately  after  removal  of  two-thirds  of  the 
pancreas  and  persisted  until  death  three  days  later. 

Various  operations  have  been  undertaken  with  the 
purpose  of  relieving  the  intense  jaundice  which  accom- 
panies cancer  of  the  head  of  the  pancreas.  Cholecys- 
tenterostomy  allows  the  bile  to  escape  and  at  the  same 
time  permits  its  return  to  the  intestine;  in  some  in- 
stances the  condition  of  the  patient  has  been  improved. 
Little  benefit  has  followed  cholecystotomy,  and  in  most 
instances  death  has  quickly  followed  operation.  Gastro- 
enterostomy has  been  performed  for  the  relief  of  per- 
sistent vomiting  and  other  symptoms  caused  by  compres- 
sion of  the  pylorus  or  duodenum ;  with  pancreatic  cancer 
the  common  bile  duct  and  duct  of  Wirsung  are  com- 
pressed, and  the  operation  usually  fails  to  improve  mater- 
ially the  condition  of  the  patient. 


CHAPTER  XIV. 

DEGENERATIVE    CHANGES    AFFECTING    THE    ISLANDS    OF 
LANGERHANS. 

Degenerative  changes  which  affect  the  liver,  kidney, 
and  other  parenchymatous  organs  occur  in  the  pancreas 
as  well.  The  gland  may  exliibit  fatty,  hyaline  and  amy- 
loid degeneration,  and  may  be  the  site  of  focal  necrosis. 
All  of  these  changes  exhibit  a  tendency  to  attack  the 
islands  of  Langerhans  with  greater  severity  than  the 
glandular  acini. 

Fatty  Degeneraton. — Minute  globules  of  fat,  it  has 
been  claimed,  are  constantly  found  in  the  cells  of  the 
islands  of  Langerhans.  Dogiel,^  who  first  noted  their 
presence,  thought  that  they  gave  evidence  that  the  islands 
of  Langerhans  were  parts  of  the  gland  undergoing  de- 
generation. Stangi,^  employing  osmic  acid,  found  a  few 
particles  of  fat  in  the  islands  of  Langerhans  of  foetuses 
and  of  new-born  infants,  and  at  the  same  time  found  an 
occasional  globule  in  the  outer  zone  of  the  glandular  cells. 
With  increase  of  age  the  quantity  of  fat  was  found  to 
increase,  so  that  in  old  individuals  fat  had  become  abun- 
dant in  the  cells  of  the  acini  and  of  the  islands  of  Lan- 
gerhans, and  was  present  even  in  centro-acinar  cells  and 
in  the  epithelial  cells  of  the  ducts.  Weichselbaum  and 
Stangl  ^  found  more  fat  in  the  islands  of  Langerhans  in 
individuals  who  had  died  with  diabetes  mellitus  than  in 

'  Dogiel :  Arch,  f .  Anat.  u.  Physiol.,  Anat.  Abt.,  1893,  117. 
'  Stangl :  Wiener  klin.  Woch.,  1901,  xiv,  964. 

^  Weichselbaum  and  Stangl :    Wiener  klin.  Woeh.,  1901,  xiv,  968. 

299 


300  DISEASE  OF  THE  PANCREAS 

other  individuals  of  the  same  age ;  but  since  fat  is  present 
in  the  normal  pancreas,  they  attribute  little  importance 
to  this  observation. 

The  observations  of  Symmers"*  who  has  employed 
Sudan  III  as  a  stain  do  not  wholly  agree  with  those  of 
Stangl,  for  in  forty-nine  subjects  varying  from  seven 
months  of  fetal  life  to  sixty-eight  years  of  age  no  fat 
has  been  found  in  the  islands  of  Langerhans,  or  fat  has 
been  present  in  trivial  amount.  In  twenty-four  individ- 
uals, on  the  contrary,  fat  has  occurred  as  minute  granule- 
like particles  or  as  globules,  and  has  been  so  abundant 
that  the  islands  of  Langerhans  have  been  conspicuous 
as  red  points  under  the  low  power  of  the  microscope. 
Symmers  believes  that  prolonged  use  of  alcohol  pro- 
duces fatty  degeneration  of  the  islands  of  Langerhans, 
for  in  twenty-four  of  thirty-two  individuals  who  had  used 
alcohol  in  excess  the  islands  of  Langerhans  have  exhibited 
this  change,  whereas  it  has  been  absent  in  forty-one 
individuals  who  have  given  no  history  of  alcoholic 
indulgence. 

Hyaline  Degeneration. — The  lesions  of  the  pancreas 
previously  described  do  not  exhibit  a  tendency  to  attack 
and  destroy  the  islands  of  Langerhans,  leaving  uninjured 
the  secreting  parenchyma.  With  the  interacinar  type  of 
chronic  interstitial  pancreatitis  these  structures  are  in- 
vaded, but  the  remaining  glandular  parenchyma  is  almost 
equally  affected.  One  form  of  degeneration,  however, 
exhibits  a  specific  tendency  to  select  and  destroy  the 
interacinar  islands,  and  in  most  cases  leaves  the  secreting 
parenchyma  almost  unaffected. 

*  Symmers:    Arch,  of  Inter.  Med.,  1909,  iii,  279. 


DEGENERATIVE  CHANGES  301 

In  a  considerable  number  of  cases  the  pancreas  has 
been  found  to  be  the  seat  of  a  peculiar  hyaline  change 
which  destroys  the  islands  of  Langerhans.  The  associa- 
tion of  diabetes  mellitus  with  the  lesion  has  given  much 
interest  to  its  study.  This  peculiar  transformation 
affecting  the  islands  of  Langerhans  belongs  to  the  varied 
and  ill-defined  group  of  degenerative  processes  of  which 
the  common  character  is  the  formation  of  a  homogeneous 
or  hyaline  material.  This  substance  stains  with  acid 
dyes,  such  as  eosin  and  picric  acid,  but  does  not  give  the 
reactions  of  amyloid,  though  it  resists  the  action  of  a 
variety  of  solvents,  for  example,  strong  acids  and  alka- 
lies. These  characters  have  been  used  by  Von  Eeckling- 
hausen  to  group  together  products  of  cell  degeneration 
occurring  in  widely  different  tissues,  and  doubtless  repre- 
senting a  variety  of  essentially  different  processes,  which 
even  yet  have  received  no  satisfactory  classification. 

Several  years  ago  I  had  the  opportunity  of  studying 
the  pancreas  from  a  girl  who  for  two  years  before  her 
death  had  suffered  with  diabetes  mellitus.^  The  organ 
is  the  seat  of  a  lesion  which  has  destroyed  a  consider- 
able proportion  of  the  parenchyma.  The  process  which 
has  the  character  of  hyaline  degeneration,  though  not 
confined  to  the  islands  of  Langerhans,  has  so  completely 
altered  them  that  they  are  not  recognizable.  The  lesion 
is  so  remarkable  and  its  assocation  with  diabetes  of  such 
interest  that  the  following  details  are  given : 

Case  XXIX. — The  patient,  a  girl,  aged  seventeen  years,  was  in 
the  care  of  Dr.  James  Carey  Thomas.  The  onset  of  symptoms  of  the 
fatal  illness  occurred  two  years  before  death  with  extreme  thirst  and 

"  Opie :  Jour,  of  Exper.  Med.,  1901,  v,  397. 


302  DISEASE  OF  THE  PANCREAS 

polyuria;  sugar  was  found  in  the  urine  and  was  constantly  present  in 
large  amount  until  death!  Upon  diabetic  diet  the  sugar  diminished 
in  amount  but  did  not  disappear.  Marked  loss  of  body  weight  was 
not  noted.  Death  occurred  with  coma,  which  appeared  suddenly  and 
lasted  hardly  more  than  twenty-four  hours.  At  autopsy  the  only  lesion 
noted  was  that  affecting  the  pancreas;  the  entire  organ  was  preserved 
for  microscopic  study  and  kindly  given  to  me  by  Dr.  Flexner,  who 
performed  the  autopsy. 

Microscopic  Examination  of  the  Pancreas. — The  organ  is  in  large 
part  self -digested.  In  the  tail,  however,  several  areas  where  the  tissue 
is  well  preserved  give  a  clear  histological  picture  of  the  lesions  which 
are  present.  The  interstitial  tissue  is  increased  only  in  several  small 
areas.  Throughout  the  organ,  readily  distinguishable  even  in  the 
most  digested  parts  of  the  gland,  are  very  conspicuoas,  sharply  defined, 
round  or  oval,  hyaline  areas  embedded  in  the  parenchyma;  they  vary 
considerably  in  size.  Where  the  parenchyma  stains  deeply  with  hsema- 
toxylin  these  areas  stand  out  conspicuously  as  almost  completely  un- 
stained foci.  Their  structure  is  as  follows  (Fig.  43)  :  Coarse,  tortuous, 
hyaline  columns  separate  strands  of  tissue,  containing  nuclei  and  repre- 
senting, in  part  at  least,  capillary  endothelium,  from  compressed  rows  of 
epithelial  cells,  evidently  atrophied  parenchymatous  cells.  The  hyaline 
material  lies  immediately  outside  the  capillary  wall,  between  capillary 
and  adjacent  epithelial  cells.  Occasionally  the  lumen  of  the  capillary 
is  visible  and  may  contain  shadows  of  red  corpuscles. 

Epithelial  cells  between  the  tortuous  hyalme  columns  form  com- 
pressed rows  vaiying  in  width.  The  cells  which  are  diminished  in  size 
are  usually  an-anged  in  columns.  Rarely  within  the  area  of  hyaline 
change,  most  frequently  in  its  periphery,  are  cells  grouped  about  a 
well-defined  lumen.  Islands  of  Langerhaiis  are  not  recognizable.  The 
hyaline  material  does  not  stain  by  Weigert's  method  for  the  staining 
of  fibrin.  Reactions  for  amyloid  have  not  been  obtained  with  specimens 
hardened  in  alcohol. 

Microscopic  Examination  of  other  Organs.— The  liver,  kidneys  and 
other  organs  exhibit  no  noteworthy  abnorinality ;  tiie  blood-vessels  are 
normal. 


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Fig.  43. — Hyaline  degeneration  of  tlie  pancreas.      (Case  XXIX.) 


DEGENERATIVE  CHANGES  303 

The  remarkable  lesion  just  described  has  apparently- 
obstructed  the  vascular  supply  of  a  large  proportion  of 
the  pancreatic  parenchyma.  Newly-formed  hyaline  ma- 
terial is  deposited  between  the  capillaries  and  the  paren- 
chymatous cells  (Fig.  43).  Since  the  tissue  examined 
has  been  hardened  in  95  per  cent,  alcohol  the  absence 
of  reactions  for  amyloid  is  not  conclusive.  That  the 
lesion  is  not  this  form  of  degeneration  is  shown  by  the 
absence  of  similar  change  in  other  organs  which  are  sub- 
ject to  more  advanced  amyloid  degeneration  than  the 
pancreas. 

In  the  tail  of  the  pancreas  areas  of  hyaline  transfor- 
mation are  larger  and  more  numerous  than  elsewhere, 
involving  at  least  two-thirds  of  the  sectional  area. 
Though  the  remainder  of  the  parenchyma  is  in  a  fair 
state  of  preservation,  islands  of  Langerhans  are  not 
found.  The  absence  of  recognizable  islands  of  Langer- 
hans in  the  tail  is  especially  remarkable  when  we  remem- 
ber that  they  are  normally  most  abundant  in  this  part 
of  the  organ.  It  is  evident,  therefore,  that  the  lesion  has 
implicated  these  structures ;  but  that  it  is  not  confined  to 
them  is  shown  by  the  extent  and  abundance  of  the  affected 
areas.  Often  the  latter  correspond  in  size  and  shape 
to  these  islands,  but  they  may  be  several  times  as  large. 
The  occurrence  of  epithelial  cells  arranged  about  a  lumen, 
particularly  at  the  periphery  of  the  altered  tissue,  shows 
that  acini  as  well  as  interacinar  islets  are  affected.  In 
the  head  and  body  of  the  gland,  areas  of  hyaline  trans- 
formation are  less  abundant  and  smaller,  usually  cor- 
responding in  size  to  islands  of  Langerhans.  Unfor- 
tunately, self-digestion  of  these  parts  of  the  organ 
prevents  recognition  of  very  early  stages  of  the  lesion 
and  of  their  relation  to  the  various  histological  elements. 


304  DISEASE  OF  THE  PANCREAS 

In  a  second  case  ^  of  diabetes  the  localization  of 
hyaline  degeneration  in  the  islands  of  Langerhans  has 
been  clearly  demonstrated;  these  bodies  are  the  seat  of 
a  degenerative  change  which  has  left  almost  unaltered  the 
secreting  parenchyma  of  the  gland.  The  lesion,  pre- 
viously undescribed,  demonstrates  very  clearly,  as  will 
be  shown  later,  the  relationship  of  diabetes  mellitus  to 
the  islands  of  Langerhans. 

Case  XXX. — The  patient,  a  negro  woman,  aged  fifty-four  years, 
was  admitted  to  the  Johns  Hopkins  Hospital,  in  the  service  of  Dr. 
Osier,  complaining  of  cough.  Her  present  illness  began  about  eleven 
months  before  her  admission,  when,  she  states,  she  had  a  severe  cold 
which  became  steadily  worse.  She  has  lost  much  weight.  Several 
months  after  the  onset  of  cough  her  urine  increased  in  quantity,  so 
that  for  a  time  she  was  compelled  to  void  it  almost  every  hour  during 
the  night.  At  the  same  time  she  experienced  great  hunger  and  thirst, 
and  ate  and  drank  enormously.  These  symptoms  lasted  during  part 
of  the  spring  and  summer,  and  disappeared  some  months  before  her 
admission  to  the  hospital.  She  had  recently  voided  the  usual  amount 
of  urine,  and  there  was  no  excessive  hunger  or  thirst. 

When  admitted  the  patient  was  thin  but  moderately  well  nourished. 
Signs  of  consolidation  were  found  at  the  apices  of  both  lungs,  and 
tubercle  bacilli  were  demonstrated  in  the  sputum.  The  stools  were  of 
normal  color  and  contained  no  fat.  The  patient  gradually  became 
weaker  and  death,  which  occurred  on  the  seventh  day  after  admission, 
was  not  preceded  by  coma. 

The  specific  gravity  of  the  urine  varied  between  1025  and  1035. 
It  contained  sugar  in  abundance,  but  neither  albumin  nor  casts.  On 
the  fourth  day  after  admission  880  c.c.  were  collected;  the  specific 
gravity  was  1028,  and  4  per  cent,  of  sugar  was  present.  On  the 
following  day  the  amount  was  1200  c.c,  the  specific  gravity  1035, 
and  the  quantity  of  sugar  5.4  per  cent. 

Autopsy. — The  body  is  that  of  a  sparely  nourished  woman,  and 

'  Opie :  Jour,  of  Exper.  Med.,  1901,  v,  527. 


DEGENERATIVE  CHANGES  305 

subcutaneous  fat  is  present  in  small  amount.  The  heart  is  normal  in 
appearance;  within  the  coronary  arteries  near  their  orifices  are;  a 
few  slightly  raised,  yellow  patches.  Occupying  the  upper  part  of  the 
upper  lobe  of  the  left  lung  is  a  large,  irregular  cavity;  the  remainder 
of  the  lobe  is  consolidated,  and  riddled  with  small  cavities.  The  upper 
part  of  the  lower  lobe  is  very  thickly  studded  with  groups  of  confluent, 
partly  caseous  tubercles.  At  the  apex  of  the  right  lung,  below  the 
pleura,  is  a  cavity,  which  in  size  and  appearance  resembles  that  of  the 
left  lung. 

The  liver  is  pale,  and  upon  the  cut  surface  are  seen  yellowish  tuber- 
cles of  minute  size.  The  spleen  is  not  enlarged.  The  kidneys  are  large, 
and  weigh  together  400  Gm.  The  surface,  after  removal  of  the  capsule, 
is  smooth  and  pale.  In  the  lower  part  of  the  ileum  and  in  the  large 
intestine  are  a  few  superficial  ulcers,  with  irregular,  slightly  raised 
edges. 

The  pancreas,  which  weighs  80  Gm.,  can  be  readily  dissected  from 
the  surrounding  tissues.  It  is  soft  in  consistence,  on  section  has  a 
grayish-yellow  color,  and  appears  to  be  normal. 

The  intima  of  the  aorta,  though  fairly  smooth,  is  studded  with 
irreg^ar,  slightly  raised  plaques.  The  arteries  at  the  base  of  the  brain 
are  normal  in  appearance.  No  lesion  of  the  brain  is  found;  the  floor 
of  the  fourth  ventricle  presents  nothing  unusual. 

In  sections  prepared  for  histological  study  from  the 
pancreas  of  the  case  just  described,  is  found  no  general- 
ized increase  of  the  interstitial  tissue,  but  here  and  there, 
particularly  in  the  tail  of  the  organ,  the  fibrous  stroma 
shows  some  proliferation,  and  there  are  irregularly- 
distributed  strands  of  tissue  between  the  acini.  This 
scanty  newly-formed  interstitial  tissue,  where  it  occurs, 
is  poor  in  cells,  but  about  some  of  the  medium-sized  inter- 
lobular blood-vessels  are  small  accumulations  of  lymphoid 
cells,  together  with  an  occasional  plasma  cell.  The  ducts 
are  not  dilated  and  appear  to  be  normal.  There  are  no 
alterations  of  the  veins  or  arteries. 

20 


306  DISEASE  OF  THE  PANCREAS 

The  islands  of  Langerhans  are  the  seat  of  a  remark- 
able change  (Fig.  44).  In  varying  amount  within  almost 
every  island  of  Langerhans  is  a  homogeneous  material 
which  stains  with  eosin.  Earely  is  an  interacinar  island 
found  unaltered.  Those  which  are  least  changed  contain 
a  few  scattered  masses  of  hyaline  material,  of  which  the 
smallest  are  irregularly  polygonal  in  shape  and  corre- 
spond in  size  to  the  cells  of  the  island;  the  larger  par- 
ticles are  rounded.  This  hyaline  substance  at  times  lies 
in  the  midst  of  groups  of  cells,  but  is  usually  in  contact 
with  the  capillaries  of  the  island,  or  next  the  peripheral 
fibrous  tissue,  and  is  therefore  between  the  remaining 
cells  and  the  capillary  walls.  Increasing  in  amount,  it 
replaces  the  cells  and,  where  it  is  abundant,  the  cells 
which  still  persist  are  small  and  contain  small  nuclei, 
staining  deeply  with  haematoxylin ;  but  they  do  not  appear 
compressed  or  distorted. 

In  islands  of  Langerhans,  in  which  the  lesion  is  more 
advanced,  hyaline  material  occurs  as  conspicuous  masses 
in  contact  with  capillaries,  the  endothelium  of  which  is 
well  preserved.  It  does  not  form  a  uniform  zone  about 
them,  but  occurs  as  scattered  groups  of  irregular, 
rounded,  often  globular  masses  (Fig.  45).  The  cells 
of  the  island  have  been  in  large  part  replaced,  and  be- 
tween the  hyaline  particles  is  seen  only  an  occasional 
compressed,  fusiform,  or  irregular  nucleus. 

The  hyaline  substance  may  occupy  almost  the  entii"« 
area  of  the  island,  and  besides  a  few  endothelial  cells 
are  found  only  small  scattered  groups  or  rows  of  atro- 
phic epithelial  cells.  The  island  is  represented  by  a 
sharply  circumscribed  hyaline  structure,  composed  of 
particles  of  homogeneous  material,  giving  the  impres- 


Fig.  44. — Drawing  made  with  low  magnification,  showing  hyaline  transformation  of  the  islands 

of  Langerhans. 


Fig.  45. — Drawing  made  with  a  higher  magnification,  showing  an  island,  cells  of  which  are 
partly  transformed  into  hyaline  material. 


DEGENERATIVE  CHANGES  307 

sion  of  broken,  twisted  columns,  between  which  are  capil- 
lary walls.  The  nuclei  of  the  capillary  endothelium 
persist  after  destruction  of  the  epithelial  cells,  but  finally 
disappear.  The  lumen  of  the  capillary  remains  patent, 
and  red  blood-corpuscles  are  seen  between  the  hyaline 
masses,  although  the  endothelium  no  longer  contains 
nuclei.  The  hyaline  metamorphosis  is  limited  strictly 
to  the  islands  of  Langerhans,  the  glandular  acini  remain- 
ing intact. 

Lesions  similar  to  those  of  the  pancreas  are  not  pres- 
ent in  other  organs.  The  blood-vessels  of  the  liver, 
spleen,  and  kidney  are  apparently  unaltered,  and  there 
is  no  formation  of  hyaline  material  in  these  organs. 

The  peculiarly  localized  lesion  observed  in  the  pre- 
ceding cases  of  diabetes  demonstrates,  I  believe,  a  causal 
relationship  between  alterations  of  the  islands  of  Langer- 
hans and  the  disease  diabetes  mellitus;  this  relationship 
will  be  discussed  in  a  later  chapter.  Since  this  charac- 
teristic lesion  had  not  been  described,  its  occurrence  was 
at  first  thought  to  be  rare,  but  in  addition  to  cases  which 
I  have  recorded  other  observers  studying  the  pathology 
of  diabetes  have  noted  similar  changes,  so  that  the  asso- 
ciation of  the  two  conditions  cannot  be  regarded  as 
uncommon. 

In  the  two  cases  to  follow  the  islands  of  Langerhans 
were  the  seat  of  destructive  changes  comparable  to  those 
present  in  Case  XXX,  but  the  secreting  parenchyma  was 
somewhat  more  altered,  exhibiting  in  one  instance  slight 
in  the  other  advanced  interacinar  pancreatitis. 

Case  XXXI. — The  patient,  male,  colored,  aged  forty-eight  years, 
was  admitted  to  the  Johns  Hopkins  Hospital  in  order  that  an  operation 
for  cataract  might  be  performed.     Tor  six  or  seven  years  he  had  been 


808  DISEASE  OF  THE  PANCREAS 

troubled  with  dimness  of  vision.  No  evidence  of  syphilis  nor  of  alco- 
holic excess  was  obtainable.  Shortly  after  the  operation  the  patient 
became  comatose.  Sugar  (4  per  cent.),  acetone  and  diacetic  acid  were 
present  in  the  urine.     The  patient  died  at  the  end  of  two  days. 

Anatomical  diagnosis. — Hyaline  degeneration  of  the  islands  of 
Langerhans.  Hypertrophy  of  the  kidneys;  (slight)  chronic  diffuse 
nephritis;  chronic  catarrhal  gastritis;  oedema  of  lungs. 

The  pancreas,  weighing  61.5  Gm.,  is  flaccid  and  appears  to  be 
normal.  Microscopical  examination  shows  a  slight  increase  of  the 
interacinar  connective  tissue,  though  in  many  places,  particularly  in 
the  head  of  the  gland,  the  interstitial  tissue  is  normal.  Throughout 
the  organ  islands  of  Langerhans  exhibit  almost  universally,  but  in 
varying  degree,  the  hyaline  change  already  described.  Where  epithelial 
cells  are  almost  wholly  replaced,  the  hyaline  substance  has  acquired  an 
unusually  homogeneous  appearance  and  forms  globular  masses,  which 
are  compressed  into  tortuous  columns  lying  beside  the  capillary  vessels 
of  the  island. 

Case  XXXII. — The  patient,  male,  seventy-three  years  of  age, 
was  admitted  to  the  service  of  Dr.  Osier.  There  was  no  history  of 
syphilis  nor  of  alcoholic  excess.  About  ten  months  before  his  death, 
when  first  admitted  to  the  Hospital,  sugar  was  found  in  the  urine 
(1.9  to  4.5  per  cent.),  the  total  amount  excreted  in  twenty-four  hours 
being  from  29  to  49.3  Gm.  When  given  a  diet  free  from  carbohydrates 
sugar  disappeared  from  the  urine.  The  patient  was  again  admitted 
to  the  Hospital  nineteen  days  before  death.  There  was  pulmonary 
tuberculosis.  The  urine  contained  3.6  per  cent,  sugar,  but  shortly 
before  death  glycosuria  disappeared. 

Anatomical  Diagnosis. — Hyaline  degeneration  of  the  islands  of 
Langerhans  with  chronic  interacinar  pancreatitis.  Pulmonary  tuber- 
culosis; chronic  diffuse  neiDhritis;  thrombosis  of  the  left  femoral  and 
cominon  iliac  veins  and  of  the  left  pulmonai-y  artei-y;  general  arterial 
sclerosis. 

The  pancreas,  weighing  120  Gm.,  is  firm  in  consistence,  and  fat 
is  abundant  between  the  lobules.  In  the  wall  of  the  stomach  is  a 
ttodule  of  pancreatic  tissue  (described  as  Specimen  IV  in  Chap.  II). 

Microscopic  examination  shows  that  fat  is  abundant  in  the  inter- 


DEGENERATIVE  CHANGES  309 

stitial  tissue  of  the  pancreas,  penetrating  in  many  places  between  tlie 
acini.  Throughout  the  organ  there  is  a  moderate  irregularly  dis- 
tributed increase  of  the  interstitial  tissue  between  the  acini.  Islands 
of  Langerhans  are  the  seat  of  hyaline  degeneration  similar  to  that 
already  described.  In  the  tail  they  are  almost  universally  altered.  The 
change  in  many  instances  is  so  far  advanced  that  the  epithelial  cells 
are  almost  completly  replaced  by  hyaline  substance. 

In  the  following  case  diabetes  was  of  mild  type,  and 
glycosuria  disappeared  when  the  patient  was  given  a 
diet  poor  in  carbohydrates.  Changes  in  the  pancreas, 
though  present,  were  less  extensive  than  in  the  preceding 
cases,  and  only  a  few  islands  of  Langerhans  were  the 
seat  of  advanced  hyaline  changes.  ■ 

Case  XXXIII. — The  patient,  male,  white,  aged  fifty-one  years, 
denies  venereal  disease;  he  has  been  in  the  habit  of  drinking  daily 
several  pints  of  beer  and  sour  wine.  The  present  illness  began  with  a 
cough  about  a  year  and  a  half  before  its  fatal  termination;  tubercle 
bacilli  were  found  in  the  sputum.  On  three  occasions  the  patient  was 
admitted  to  the  service  of  Dr.  Osier  and  the  urine  contained  from 
3  to  8  per  cent,  of  sugar,  but  with  rest  in  bed  and  a  diet  free  from 
carbohydrates  glycosuria  disappeared. 

Anatomical  Diagnosis. — Hyaline  degeneration  of  the  islands  of 
Langerhans  with  chronic  interacinar  pancreatitis.  Chronic  pulmonary 
tuberculosis;  general  arterial  sclerosis;  chronic  diffuse  nephritis;  focal 
necrosis  of  the  liver. 

The  pancreas,  which  weighs  65  Cm.,  is  fairly  firm  in  consistence. 
The  splenic  artery  is  thickened  and  tortuous  and  its  intima  shows  raised 
sclerotic  plaques.  Microscopic  examination  of  the  pancreas  shows 
diffuse  increase  of  the  interacinar  stroma  most  advanced  in  the  tail. 
Islands  of  Langerhans  are  fairly  abundant,  and  in  most  instances  show 
no  alteration,  but  occasionally  they  are  surrounded  and  penetrated 
by  thickened  strands  of  connective  tissue.  In  the  tail  are  found  inter- 
acinar islands  which  contain  hyaline  material,  while  in  several  instances 
almost  complete  hyaline  transformation  has  oceun-ed. 


310  DISEASE  OF  THE  PANCREAS 

By  means  of  staining  reactions,  P.  Ernst '^  lias  at- 
tempted to  demonstrate  that  tlie  various  substances 
grouped  together  by  Von  Recklinghausen  ^  as  hyaline  are 
not  chemically  identical.  Hyaline  material  which  is  de- 
rived from  epithelial  cells  stains  orange-yellow  with 
Van  Gieson's  stain,  being  colored  by  picric  acid,  and  only 
tinted  by  fuchsin,  while  that  which  is  formed  in  connective 
tissue  is  stained  deep  red  by  fuchsin. 

Lubarsch  ^  regards  the  staining  reactions  of  Ernst  as 
an  uncertain  means  for  the  identification  of  different 
hyaline  substances,  but  admits  that  the  method  employed 
indicates  in  many  cases  the  origin  of  hyaline  material. 
Normal  fibrous  tissue  is  stained  intensely  red  by  acid 
fuchsin,  and  the  substances  upon  which  depend  its  affinity 
for  the  dye  are  present  in  hyaline  material  derived 
from  fibrous  tissue.  Pure  hyaline,  whatever  its  origin, 
Lubarsch  suggests,  always  stains  in  the  same  way,  while 
differences  in  staining  reaction  are  dependent  upon  the 
admixture  of  other  substances.  Following  Lubarsch,  we 
may  distinguish  hyaline  of  epithelial  origin  and  hyaline 
derived  from  connective  tissue,  and,  again,  we  may  recog- 
nize hyaline  which,  like  the  colloid  of  the  thyroid  gland, 
is  formed  outside  of  cells,  presumably  by  a  process  of 
secretion,  and  hyaline  which  is  formed  by  transformation 
of  the  cell  protoplasm. 

The  material  which  in  the  cases  herewith  described 
partly  or  completely  replaces  the  islands  of  Langerhans 


'  Ernst :  Virchow's  Arch.,  1892,  cxxx,  377. 

'  Von  Recklinghausen :  Handbuch  der  allgemeinen  Pathologie  des 
Krieslaufs  und  der  Ernahrung,  Deutsche  Chirurgie.     Stuttgart,  1883. 

•  Lubarsch :  Ergebn.  der  allg.  Path.  u.  path,  Anat.,  herausgeg.  von 
Lubarsch  u.  Ostertag.,  1895,  i,  Abt.  ii,  200. 


DEGENERATIVE  CHANGES  311 

was  tested  with  a  variety  of  agents  which  have  been  used 
in  the  study  of  hyaline  substances.  It  stains  deeply  with 
acid  dyes,  like  eosin  and  picric  acid,  but  shows  little 
affinity  for  nuclear  stains,  as,  for  example,  haematoxylin 
and  methylene  blue. 

The  reactions  of  amyloid  are  not  obtained  with  iodine, 
nor  with  gentian  violet,  methyl  violet,  nor  iodine  green. 
The  material  does  not  stain  by  Weigert's  method  for  the 
demonstration  of  fibrin. 

Of  much  interest,  in  view  of  the  study  of  Ernst,  is  the 
behavior  of  the  substance  toward  picric  acid  and  acid 
fuchsin.  It  stains  with  picric  acid,  but  shows  no  affinity 
for  acid  fuchsin.  The  material,  therefore,  conducts  itself 
toward  Van  Gieson's  stain  as  does,  according  to  Ernst, 
hyaline  of  epithelial  origin,  and  it  is  improbable  that  it 
is  formed,  as  Weichselbaum  and  Stangl  believe,  by  trans- 
formation of  newly-formed  fibrous  tissue  within  the 
islands  of  Langerhans. 

Is  the  hyaline  material  formed  by  a  process  resem- 
bling secretion,  or  is  it  formed  from  the  protoplasm  of 
degenerate  cells'? 

By  the  use  of  certain  stains — namely,  phosphomolyb- 
dic  acid  haematoxylin  by  the  method  of  Eibbert  for  white 
fibrous  tissue  or  aniline  blue  as  employed  by  Mallory  for 
the  demonstration  of  white  fibres  and  reticulum — the 
hyaline  material  acquires  a  deep-blue  color  and  becomes 
very  conspicuous.  When  some  islands  of  Langerhans  of 
a  gland  exhibit  hyaline  degeneration  there  are  not  infre- 
quently found  in  other  islands  slightly  enlarged  cells, 
which,  though  still  containing  nuclei,  exhibit  a  reaction 
similar  to  that  of  the  hyaline  material;  the  cell  proto- 


312  DISEASE  OF  THE  PANCREAS 

plasm,  wliicli  is  still  granular,  has  assumed  a  diffuse 
blue  color. 

The  degenerative  process  first  manifests  itself  by  an 
increase  in  the  size  of  the  cell  and  an  alteration  of  its 
protoplasm.  With  the  death  of  the  cell  its  nucleus  dis- 
appears, and  the  protoplasm  which  stains  with  acid  dyes 
remains  for  a  time  granular,  but  subsequently  becomes 
homogeneous.  These  small  particles  of  hyaline  fuse  with 
one  another  and  form  larger  masses  which  lie  in  contact 
with  the  fibrous  septa  of  the  island.  After  complete 
transformation  of  its  cells  the  island  is  represented  by  a 
hyaline  mass  penetrated  by  the  remains  of  altered 
capillaries. 

Since  the  publication  of  Cases  XXIX  and  XXX  hya- 
line degeneration  of  the  islands  of  Langerhans  accom- 
panying diabetes  has  been  described  by  many  writers. 
Among  two  hundred  and  eighty-eight  cases  of  diabetes 
collected  from  the  literature  of  the  subject  the  lesion 
occurred  forty-one  times  (see  Chap.  XV) ;  among  ninety 
cases  of  diabetes  studied  by  Cecil  ^^  islands  of  Langer- 
hans were  hyaline  in  twenty-seven.  The  cases  which  have 
been  described  do  not  explain  its  cause;  it  is  almost 
equally  common  in  men  and  in  women  (twenty-nine  cases 
with  sex  recorded  were  in  men  and  twenty-five  in  women). 
The  lesion  is  uncommon  between  the  ages  of  ten  and 
forty  years,  whereas  in  two- thirds  of  the  cases  the  age 
is  between  forty  and  seventy  years. 

Hyaline  degeneration  is  usually  accompanied  by  inter- 
acinar  pancreatitis.  Increase  of  interstitial  tissue  is 
often  slight,  and  in  some  instances  hyaline  degeneration 
of  the  interacinar  islands  has  occurred  in  an  otherwise 

"  Loc.  cit. 


DEGENERATIVE  CHANGES  313 

normal  pancreas.  In  cases  of  Wright  and  Joslin,^^ 
SchmidV^  Herzog/^  Miiller,^^  Norris  ^-^  and  Cecil  there 
was  no  increase  of  the  interstitial  tissue  of  the  gland. 
In  Cases  XXX  and  XXXI  this  increase  of  interstitial 
tissue  is  so  insignificant  that  it  is  recognizable  only 
in  certain  parts  of  the  gland.  The  relationship  of 
hyaline  degeneration  of  the  interacinar  islands  to  inter- 
stitial changes  occurring  in  the  secreting  parenchyma 
is  doubtful.  Since  large  readily  injected  capillaries 
enter  the  islands  of  Langerhans,  and  subsequently  anas- 
tomose freely  with  capillary  vessels  of  the  surrounding 
acini,  it  is  possible,  though  not  demonstrable,  that  inter- 
ference with  the  circulation  in  the  interacinar  islands  may 
disturb  the  nutrition  of  the  surrounding  parenchyma. 
On  the  other  hand,  it  is  not  improbable  that  both  pro- 
cesses are  the  result  of  an  irritant  carried  to  the  pancreas 
by  the  blood.  In  Case  XXIX,  though  the  lesion  has 
destroyed  the  islands  of  Langerhans,  it  has  overstepped 
their  limits  and  implicates  in  wide-spread  destruction  the 
secreting  parenchyma  as  well.  In  the  other  cases  the 
hyaline  change  exhibits  a  remarkable  tendency  to  limit 
itself  to  the  interacinar  islands. 

Arterial  sclerosis  has  been  present  in  a  considerable 
number  of  individuals  who  have  exhibited  the  lesion;  in 
all  save  two  of  the  cases  described  by  Cecil  the  arteries 
of  the  pancreas  have  been  sclerotic. 

Amyloid  Degeneration  of  the  Pancreas. — ^With  gen- 
eral amyloid  disease,  amyloid  is  occasionally  recognizable 

"  Wright  and  Joslin :  Jour,  of  Med.  Res.,  1901,  vi,  360. 

"  Schmidt :  Miinchener  med.  Woch.,  1902,  xlix,  51. 

"Herzog:  Virchow's  Arch.,  1902,  clxviii,  83, 

"Miiller:  Inaug.  Diss.,  Berlin,  1905. 

""  Norris :  Trans,  of  the  New  York  Path.  Soc,  1907,  vii,  19. 


314  DISEASE  OF  THE  PANCREAS 

upon  the  cut  surface  of  the  pancreas  after  application  of 
solutions  containing  iodine,  and  although  the  lesion  does 
not  attain  the  severity  often  seen  in  the  liver,  spleen,  and 
kidney,  microscopic  examination  usually  demonstrates  its 
presence  when  these  organs  are  affected.  Friedreich  ^® 
found  the  change  in  the  interlobular  arteries  and  in  the 
interacinar  capillaries  of  the  gland  and  Kyber  ^'  noted 
similar  changes  in  every  instance  of  amyloid  disease  in 
which  he  examined  the  pancreas.  Birch-Hirschfeld  ^^ 
has  carefully  studied  the  localization  of  the  lesion  and 
has  noted  the  presence  of  amyloid  in  the  walls  of  the 
capillaries  within  the  islands  of  Langerhans.  In  two 
cases  of  pulmonary  tuberculosis  Reitmann  ^^  found  simi- 
lar localization  of  amyloid  in  many  islands  of  Langer- 
hans ;  the  cells  were  reduced  in  size  and  in  part  destroyed. 

With  metachromatic  stains  usually  employed  for' 
demonstration  of  amyloid  (gentian  violet,  methyl  green, 
etc.)  Butterfield -'^  has  studied  the  distribution  of  the 
lesion  in  four  cases  of  amyloid  disease;  in  two  of  these 
cases  the  lesion  has  been  recognized  at  autopsy  by  use  of 
iodine.  In  three  instances  there  has  been  increase  of  the 
interlobular  tissue  of  the  gland.  Amyloid  is  deposited 
in  the  walls  of  the  small  interlobular  arteries,  in  the  walls 
of  the  capillaries  of  the  islands  of  Langerhans  and  occa- 
sionally in  patches  in  the  walls  of  small  veins. 

Focal  Necrosis  of  the  Pancreas. — In  a  case  of  diabetes 
I  have  found  a  lesion  of  the  pancreas  which  differs  from 

"Friedreich:    Virchow's  Arch.,  1857,  xi,  387. 
"Kyber:  Virchow's  Arch.,  1R80,  Ixxxi,  420. 

"Birch-Hirschfeld:  Lehrbuch  der  path.  Anat.,  Leipzig,  1895,  ii, 
744. 

"  Reitmann :  Zeit.  f .  Heilk.,  1905,  xxvi,  1. 

"•  Butterfield :  Phys.  and  Surg.,  1904,  xxvii,  529. 


DEGENERATIVE  CHANGES  315 

that  present  in  the  cases  already  cited.  A  destructive 
lesion  affects  not  only  the  interacinar  islands,  causing 
death  of  their  cells,  but  has  attacked  the  secreting  paren- 
chyma as  well.  The  process  does  not  present  the  charac- 
ters of  hyaline  degeneration  already  described,  but  occur- 
ring in  foci  closely  resembles  the  coagulative  necrosis  so 
frequently  observed  in  the  liver  in  association  with  ty- 
phoid fever  and  other  infections. 

Case  XXXIV. — W.  M.,  male,  colored,  aged  forty-eight  years,  was 
admitted  to  the  serv-ice  of  Dr.  Osier  complaining  of  frequent  micturi- 
tion, great  thirst,  and  hunger,  with  which  he  had  suffered  during  three 
months.  Two  months  previously  sugar  had  been  found  in  the  urine. 
He  had  a  cough,  and  his  weight  had  diminished  from  166  to  110  pounds. 
Shortly  before  admission  to  the  Hospital  he  suddenly  became  uncon- 
scious, and  hemiplegia  affecting  the  left  side  appeared.  Death  occurred 
on  the  second  day  after  admission.  The  urine,  examined  twice,  con- 
tained 3.5  and  7  per  cent,  sugar. 

Anatomical  Diagnosis. — Pulmonary  tuberculosis  with  cavity  for- 
mation; acute  endocarditis  of  the  aortic  and  mitral  valve;  infarcts  in 
the  spleen  and  kidney;  chronic  diffuse  nephritis. 

The  pancreas  presents  no  notable  abnormality;  a  few  ecchymoses 
are  seen  below  the  surface.  Microscopic  examination  shows  a  slight 
increase  of  the  interstitial  tissue  at  the  expense  of  the  parenchyma. 
Newly-fonned  connective  tissue,  which  occurs  in  irregular  isolated 
patches  within  the  lobules,  contains  few  cells,  and  is  distended  as 
though  by  oedema.  Foci  of  necrosis  are  found  in  the  parenchyma,  and 
involve  small  areas  consisting  of  a  considerable  number  of  acini.  The 
secreting  cells  have  here  lost  their  nuclei,  and  the  cell  protoplasm  takes 
a  bright  stain  with  eosin;  the  appearance  is  that  of  coagulative  necrosis 
in  the  liver.  Within  such  an  area  is  found  in  many  instances  an  island 
of  Langerhans  which  has  undergone  an  analogous  change;  the  cells 
have  lost  their  nuclei.  Rarely  the  cells  of  an  island  have  undergone 
necrosis  while  the  surrounding  acini  are  entirely  normal.  Delicate 
interstitial  tissue  is  in  process  of  formation  within  one  focus  of  necrosis, 


316  DISEASE  OF  THE  PANCREAS 

and  it  is  not  improbable  that  the  irregularly  distributed  increase  of 
stroma  is  the  result  of  similar  degenerative  changes.  A  few  nonnal 
islands  of  Langerhans  are  found,  but  throughout  the  gland  these  struc- 
tures are  sparsely  scattered.  In  sections  from  the  head  of  the  gland 
foci  of  necrosis  are  not  found,  but  otherwise  the  tissue  resembles  that 
of  the  body;  tissue  from  the  splenic  extremity  was  not  preserved. 

Cells  of  the  islands  of  Langerhans  and  of  the  acini 
have  undergone  necrosis,  but  there  is  no  formation  of 
compact  hyaline  material,  the  presence  of  which  is  charac- 
teristic of  the  lesions  previously  observed.  The  paren- 
chymatous cells,  preserving  their  identity  for  a  time,  lose 
their  nuclei  and  stain  deeply  with  eosin.  The  process 
is  apparently  acute,  yet  throughout  the  gland  the  pres- 
ence of  beginning  chronic  inflammatory  changes  suggests 
that  the  interstitial  tissue  may  proliferate  in  order  to 
replace  defects  caused  by  destruction  of  the  parenchy- 
matous cells.  The  possibility  suggests  itself  that  patches 
of  delicate  sclerosis  represent  previous  foci  of  similar 
character.  Islands  of  Langerhans  are  implicated  in  the 
process,  and  their  number  is  much  less  than  that  usually 
found. 

"Whipple  2^  has  found  focal  necroses  in  the  pan- 
creas of  forty-one  of  two  hundred  and  thirty  subjects 
which  he  examined;  the  lesion  has  usually  occurred  in 
association  with  lobar  pneumonia  or  other  acute  bacterial 
infection.  In  small  areas  acinar  cells  are  granular  and 
have  lost  their  nuclei.  Polynuclear  leucocytes  accumu- 
late within  the  focus  of  necrosis.  At  a  later  stage 
lymphoid  cells  and  fibroblasts  show  that  newly-formed 
fibrous  tissue  may  replace  the  necrotic  parenchyma. 

"  Whipple :  Bull,  of  the  Johns  Hopkins  Hosp.,  1907,  xviii,  391. 


CHAPTER  XV. 

PATHOLOGY    OF    THE    PANCREAS    WITH    DIABETES    MELLITUS. 

Pancreatic  Diabetes. — The  experimental  studies 
which  have  been  described  have  demonstrated  the  depend- 
ence of  carbohydrate  assimilation  upon  the  pancreas,  and 
have  shown  that  its  removal  is  followed  by  a  condi- 
tion identical  with  diabetes  mellitus.  A  century  before 
the  discoveries  of  Von  Mering  and  Minkowski  the  asso- 
ciation of  diabetes  with  grave  lesions  of  the  organ  had 
been  observed,  and  since  both  conditions  are  relatively 
uncommon,  a  causal  relationship  had  suggested  itself. 

As  early  as  1788  Thomas  Cawley  ^  described  a  case 
of  diabetes  associated  with  pancreatic  calculi  and  conse- 
quent atrophy  of  the  gland.  Bright  ^  in  1833  recorded 
a  case  in  which  the  pancreas  was  the  seat  of  carcinoma 
compressing  the  duct  and  causing  atrophy.  Bouchardat  ^ 
in  1875  directed  attention  to  the  association  of  diabetes 
with  lesions  of  the  pancreas,  and  Lancereaux*  several 
years  later  claimed  that  diabetes  accompanied  by  wast- 
ing (diabete  maigre)  is  the  result  of  disease  of  the  gland, 
while  diabetes  without  wasting  (diabete  gras)  is  depen- 
dent upon  other  factors;  but  numerous  subsequent 
observations  have  failed  to  confirm  this  clinical  distinc- 
tion between  pancreatic  and  non-pancreatic  diabetes. 

The  experimental  observations  of  von  Mering  and 

'  Cawley :  London  Med.  Jour.,  1788,  286. 

'  Bright :  Med.-Chir.  Trans.,  1833,  xviii,  1. 

^Bouchardat:    De  la  glyeosurie  un  diabete  sucre.     Paris,  1875. 

*Laneereaux:    Bull.  Acad,  de  med.,  1877,  2  s.,  vi,  1215. 

317 


318  DISEASE  OF  THE  PANCREAS 

Minkowski  lia^dng  established  in  dogs  a  relationship 
between  the  pancreas  and  diabetes,  a  renewed  interest 
was  given  the  study  of  the  gland  in  this  disease.  Such 
investigation  has  shown  that  lesions  occur  in  a  consider- 
able proportion  of  cases  but  has  failed  to  demonstrate 
their  constant  presence.  On  the  one  hand,  all  cases  of 
diabetes  are  not  accompanied  by  demonstrable  lesions  of 
the  pancreas,  and  on  the  other  hand,  all  lesions  of  the 
pancreas  are  not  associated  with  diabetes. 

Hansemann,^  who  unlike  his  predecessors  supported 
the  modern  conception  of  an  internal  pancreatic  secretion, 
in  1894  collected  from  the  literature  cases  in  which  dia- 
betes was  accompanied  by  pancreatic  lesions. 

In  seventy-two  eases  of  Hansemann  the  following  alterations  of 
the  gland  occur : 

Simple  atrophy 18 

Chronic  interstitial  inflammation 18 

Pancreatic  calculi 15 

Necrosis  (post-mortem  change  in  part) 6 

Carcinoma  5 

Lipomatosis 3 

Fatty  degeneration 3 

Abscess 2 

Cyst 1 

Hyperaemia   1 

Total  72 

Such  a  summary  of  isolated  cases  reported  by  different  observers, 
in  many  instances  without  microscopic  examination  of  the  gland,  gives 
no  accurate  conception  of  the  relative  frequency  of  various  lesions; 
self-digestion  of  the  pancreas  has  been  frequently  described  as  necrosis. 
Uncommon  conditions — for  example,  calculi  and  carcinoma — are  more 
likely  to  be  reported.     There  are  also  included  a  number  of  insignificant 

'Hansemann:  Zeit.  f.  klin.  Med.,  1894,  xxvi,  191. 


PATHOLOGY  WITH  DIABETES  MELLITUS        319 

lesions — for  example,  hyperaemia  and  fatty  degeneration  of  the  paren-- 
chyma — conditions  which  are  in  a  great  majority  of  instances!  unasso- 
ciated  with  diabetes  and  are  doubtless  not  responsible  for  its  occurrence. 
Much  more  accurate  statistics  are  obtainable,  as  Hansemann  recog- 
nized from  a  series  of  consecutive  eases.  In  the  Pathological  Institute 
in  Berlin  he  studied  fifty-four  cases : 

Atrophy  (granular)   36 

Fibrous  induration   (with  hypertrophy) 3 

Complicated  case '. 1 

Normal  pancreas   8 

Condition  of  pancreas  not  noted 6 

Total 54 

In  1898  Oser '  was  able  to  collect  from  the  literature  of  the  subject 
one  hundred  and  eighty-eight  cases  of  diabetes  in  which  the  pancreas 
had  exhibited  lesions.     His  classification  of  these  lesions  is  as  follows: 

Atrophy "^8 

Induration    22 

Pancreatic  calculi    24 

Carcinoma  24 

Lipomatosis 8 

Fatty  degeneration 2 

Cyst^ 9 

Abscess 6 

Hemorrhage 3 

Necrosis   3 

Fat  necrosis 2 

Lesions  recognizable  only  by  the  microscope 7 

Total 188 

A  clue  to  the  inaccuracy  of  these  statistics  which  exaggerate  the 
relative  frequency  of  such  readily  recognizable  lesions  as  calculus  and 
carcinoma,  and  underestimate  the  frequency  of  chronic  inflammation  of 
the  gland,  is  found  in  the  last  group,  including  lesions  of  which  the 

"  Oser :  Nothnagel's  Handbuch  der  Medicin,  vol.  xviii,  Part  ii, 
Vienna,  1898, 


320  DISEASE  OF  THE  PANCREAS 

common  character  is  recognition  by  the  microscope.  Little  attention 
had  been  given  to  lesions  which  were  not  demonstrable  by  gross 
examination. 

It  has  long  been  known  that  the  pancreas  contains 
structures  which  differ  from  the  secreting  acini  and  do 
not  communicate  with  the  ducts  of  the  gland.  I  have 
shown  (1900)  that  these  bodies,  the  islands  of  Langer- 
hans,  are  diseased  in  diabetes  mellitus,  and  have  collected 
evidence  to  prove  that  lesions  of  the  islands  of  Langer- 
hans  are  accompanied  by  that  disturbance  of  carbohy- 
drate metabolism  which  follows  removal  or  destruction  of 
the  entire  pancreas.  In  the  first  edition  of  this  book  I 
recorded  nineteen  cases  of  diabetes  mellitus,  and  in  each 
instance  described  the  condition  of  the  various  histo- 
logical elements  of  the  pancreas. 

Discussion  of  the  relation  of  diabetes  mellitus  to 
lesions  of  the  islands  of  Langerhans  has  stimulated  care- 
ful study  of  the  pathology  of  the  pancreas  in  this  disease, 
and  in  consequence  a  large  number  of  cases  with  records 
of  the  histology  of  the  gland  are  available.  In  1904 
Sauerbeck  '^  was  able  to  collect  from  the  literature  of 
the  subject  one  hundred  and  seventy-six  cases  recorded 
by  observers  who  have  given  attention  to  the  changes 
affecting  secreting  acini  and  interacinar  islands.  Dur- 
ing several  years  which  have  followed  the  appearance 
of  the  article  of  Sauerbeck  one  hundred  and  twelve  cases  * 


'  Sauerbeck :  Die  Langerhansschen  Inseln  des  Pankreas  und  ihre 
Beziehung  zum  Diabetes  mellitus.  Lubarsch-Ostertag.  Ergebnisse  der 
allg.  Path.  u.  path.  Anat.,  1904,  viii,  Abt.,  ii,  538. 

*  Cases  of  Muller  (24  cases) ;  S.  Hoppe-Seyler  (7) ;  Reitmann 
(17);  Karakascheff  (16);  Finney,  Med.  Chron.,  1903,  v,  137  (8); 
Curtis,  L'Echo  med.  du  Nord.,  1902,  vi,  140  (1);  Curtis  and  Gelle 
(2) ;  Lancereaux  (4) ;  Pearee  (8) ;  MacCallum  (1) ;  Norris  (1) ;  Beat- 
tie  (1);  Lazarus  (3);  Herxheiraer  (5);  Opie  (14). 


PATHOLOGY  WITH  DIABETES  MELLITUS        321 

have  been  studied  with  the  aid  of  the  knowledge  pre- 
viously acquired.  A  review  of  these  cases,  in  which 
there  has  been  histological  examination  of  the  pancreas, 
furnishes  much  more  accurate  information  concerning 
the  pathology  of  pancreatic  diabetes  than  the  cases  of 
Oser.  There  is  wide  divergence  in  the  statistics  from  the 
two  sources. 

PANCREATIC    LESIONS. 

Interacinar  pancreatitis  (fine  sclerosis) 125    (43.4%) 

Interlobular  pancreatitis  (coarse  sclerosis) 13 

Lipomatosis  18 

Calculi    9 

Cyst    1 

Carcinoma   5 

Focal  necrosis  2 

Atrophy   65    (22.5%) 

Lesions    of    the    islands    of    Langerhans    with 
normal   parenchyma : 

Hyaline  degeneration    6 

Sclerosis 2 

Adenoma-like  hypertrophy " 3 

NO    LESION    OF    PANCREAS. 

Pancreas  normal 34  ^ 

Parenchyma  normal;  number  of  islands  of  Lan-  V  (13.5%) 

gerhans  diminished 5  J 

Total 288 

Although  these  figures  are  based  upon  a  careful  histo- 
logical study  of  the  diabetic  pancreas,  and  are  for  this 
reason  much  more  accurate  than  any  previously  obtain- 
able, they  fail  to  indicate  the  relative  frequency  of  cer- 
tain pancreatic  lesions  in  diabetes.  The  condition  of  the 
gland  which  certain  writers — for  example,  Reitmann  ^° — 

"  A&'?ociated  with  hypertrophy  of  the  secreting  acini  in  parts  of 
the  gland. 

^'Loe.  cit.,  p.  314. 
21 


322  DISEASE  OF  THE  PANCREAS 

describe  as  simple  atrophy  does  not  differ  from  that 
which  the  majority  of  authors  define  as  chronic  inflam- 
mation of  the  interacinar  type.  Included  under  the 
designation  atrophy  are  two  wholly  different  conditions. 
(a)  In  one  group  of  cases  there  is  gross  and  histological 
evidence  that  the  structural  elements  of  the  gland  have 
undergone  diminution  in  size  or  in  number,  thus  dimin- 
ishing the  size  of  the  gland  as  a  whole ;  there  is  with  this 
lesion  evidence  of  degenerative  changes  in  the  paren- 
chyma of  the  gland,  (h)  In  another  group  of  cases  the 
gland  is  smaller  than  normal,  perhaps  as  the  result  of  a 
congenital  anomaly,  and  the  histological  structure  of  the 
organ  is  unchanged.  For  the  purpose  of  classification 
this  distinction  is  important,  one  condition  being  an 
acquired  disease,  the  other  doubtless,  a  congenital 
abnormality. 

Whereas  among  one  hundred  and  thirty-nine  cases  of 
diabetes  mellitus  collected  by  Windle  "  in  1883  in  47  per 
cent,  the  pancreas  has  been  described  as  normal,  in  the 
present  series  among  two  hundred  and  eighty-eight  more 
carefully  studied  cases  only  13.5  per  cent,  have  been 
found  without  noteworthy  change  of  the  gland.  Even 
among  these  cases  there  have  been  many  in  which  the 
records  have  failed  to  indicate  that  the  organ  was  of  nor- 
mal size  and  possessed  the  various  histological  elements 
in  normal  proportion. 

The  lesion  which  is  most  common  with  diabetes  has 
been  designated  atrophy  by  one  group  and  chronic  inflam- 
mation by  another.  Some  of  these  observers  have  noted 
the  almost  invariable  implication  of  the  islands  of  Lan- 


Windle :    Dublin  Jour,  of  the  Med.  Seien.,  1883,  Ixxvi,  112. 


PATHOLOGY  WITH  DIABETES  MELLITUS        323 

gerhans  wiien  the  pancreas  is  the  seat  of  disease,  whereas 
a  smaller  number  have  described  little  alteration  of  these 
structures.  The  examination  of  a  large  number  of  cases 
by  one  observer  will  furnish  data  for  comparison  with  the 
statistics  previously  obtainable  from  the  literature  of  the 
subject.  Such  a  group  of  cases  will  determine  if,  for 
example,  so-called  simple  atrophy  of  some  writers  is  iden- 
tical with  the  lesion  described  as  chronic  inflammation 
by  others.  The  value  of  the  classification  obtained  will 
depend  upon  the  accuracy  with  which  various  lesions  are 
designated.  With  such  considerations  in  view,  Dr.  E. 
L.  Cecil  ^2  lias  studied,  in  the  Pathological  Laboratory 
of  the  Presbyterian  Hospital  of  New  York,  the  pancreas 
from  ninety  cases  ^^  of  diabetes  mellitus.  The  condition 
of  the  gland  in  these  cases  has  been  as  follows : 

Interaeinar  pancreatitis : 

With  sclerosis  of  islands  of  Langerhans 39 

With  hyaline  degeneration  of  islands  of  Langerhans 19 

With  sclerosis  of  the  islands  of  Langerhans  and  lipoma- 

.   tosis 2 

With  hyaline  degeneration  of  the  islands  of  Langerhans 

and  lipomatosis 1 

With  siderosis  of  islands  of  Langerhans   (hsemochroma- 

tosis)     2 

Total 63 

Interlobular  pancreatitis : 

With  sclerosis  of  islands  of  Langerhans 4 

Total 4 

^  Log.  cit. 

"Records  of  cases  and  tissue  from  the  pancreas  was  obtained 
from  Dr.  J.  S.  Thacher,  Dr.  J.  Homer  Wright,  Dr.  F.  B.  Mallory,  Dr. 
Libman,  Dr.  Longcope,  Dr.  Oertel,  Dr.  Charles  Norris,  Dr  Adami,  D«. 
Klotz,  Dr.  C.  W.  Duval,  Dr.  White,  Dr.  W.  G.  MacCallum,  Dr.  F.  C. 
Wood,  Dr.  Walter  James,  and  Dr.  Stein. 


324  DISEASE  OF  THE  PANCREAS 

Parenchyma  normal ;    lesions  of  islands  of  Laugerhans : 

Sclerosis  of  islands  of  Langerhans 4 

Hyaline  degeneration  of  islands  of  Langerhans 7 

Infiltration  of  leucocytes  about  islands  of  Langerhans 1 

Total 12 

Pancreas  normal  in  structure : 

Pancreas  small  and  islands  of  Langerhans  few 2 

Islands  of  Langerhans  few 3 

No  abnormality  noted 6 

Total 11 

Relation  of  Diabetes  to  Lesions  of  the  Islands  of  Lan- 
gerhans.— For  the  purpose  of  the  present  study  it  is 
pertinent  to  inquire  what  histological  changes  are  asso- 
ciated with  the  occurrence  of  diabetes.  When  a  lesion 
of  the  pancreas  is  the  cause  of  the  disease,  is  the  con 
dition  dependent  upon  changes  in  the  acini  or  in  the 
islands  of  Langerhans  or  in  both?  Total  destruction  of 
the  acini  is  often  accompanied  by  destruction  or  altera- 
tion of  the  interacinar  structures,  and  rarely  are  the 
islands  of  Langerhans  the  seat  of  marked  lesion  while  the 
acini  remain  unchanged. 

The  islands  of  Langerhans  are  composed  of  columns 
of  cells  having  no  communication  with  the  ducts  of  the 
gland,  but  in  intimate  relation  with  a  rich  capillary  net- 
work, and  an  analogous  condition  is  found  in  the  thyroid 
gland  and  in  the  adrenal.  The  pancreas,  like  these 
organs,  exerts  through  the  medium  of  the  blood  an  im- 
portant influence  on  metabolism.  Wliether  the  gland 
furnishes  some  substance  which  aids  carbohydrate 
assimilation  or  destroys  some  noxious  product  hindering 
it  is  immaterial  to  the  present  study.  When  diabetes  is 
the  result  of  pancreatic  disease,  do  the  islands  exhibit 
lesions? 


PATHOLOGY  WITH  DIABETES  MELLITUS        325 

With  the  interacinar  type  of  chronic  pancreatitis, 
which,  except  in  its  earliest  stage,  is  accompanied  by 
diabetes,  the  islands  of  Langerhans  are  invaded  by  the 
inflammatory  process.  With  the  interlobular  type,  which 
may  follow  obstruction  of  the  pancreatic  ducts  or  ascend- 
ing infection  of  the  gland,  diabetes  ensues  only  in  those 
relatively  uncommon  instances  in  which  the  lesion  has 
reached  a  very  advanced  grade;  the  sclerotic  process, 
which  in  many  cases  at  least  has  its  origin  in  the  ducts 
of  the  gland,  spares  the  islands  of  Langerhans  and  causes 
their  destruction  only  when  the  gland  is  almost  wholly 
transformed  into  dense  sclerotic  stroma.  These  facts, 
however,  do  not  demonstrate  with  certainty  the  depend- 
ence of  diabetes  upon  alterations  of  the  islands  of  Lan- 
gerhans, for  on  the  one  hand  with  interacinar  pancreatitis 
the  secreting  parenchyma  is  affected,  while  on  the  other 
hand,  with  interlobular  inflammation,  some  secreting 
alveoli  are  preserved,  even  when  the  lesion  is  far 
advanced. 

In  a  preceding  chapter  I  have  shown  the  susceptibility 
of  the  pancreas  to  hyaline  degeneration.  The  first  ex- 
ample of  this  lesion  which  came  to  my  observation  was 
accompanied  by  a  severe  type  of  diabetes,  and  though 
the  islands  were  so  altered  as  to  be  completely  unrecog- 
nizable the  secreting  parenchyma  was  in  great  part  de- 
stroyed. The  succeeding  instances  of  this  remarkable 
lesion  clearly  demonstrated  the  relationship  of  diabetes 
to  a  destructive  lesion  of  the  interacinar  islands,  for 
though  these  structures  had  undergone  very  gi'ave  altera- 
tions and  were  often  converted  into  almost  homogeneous 
hyaline  masses,  the  secreting  parenchyma,  notably  in 
Cases  XXX  and  XXXI,  showed  only  a  very  insignificant 


326  DISEASE  OF  THE  PANCREAS 

increase  of  the  stroma,  and  in  the  greater  part  of  the 
gland  was  wholly  unaltered. 

Subsequent  observations  have  demonstrated  the  sur- 
prising frequency  with  which  this  selective  lesion  accom- 
panies diabetes,  and  it  has  been  found  in  six  of  the  nine- 
teen cases  of  diabetes  previously  mentioned.  In  three 
instances,  Cases  XXX,  XXXI,  and  XXXII,  described  in 
detail,  the  lesion  of  the  islands  of  Langerhans  has  doubt- 
less been  of  such  a  character  as  to  render  them  almost 
completely  functionless,  though  the  remaining  paren- 
chyma is  relatively  well  preserved.  The  other  cases, 
including  Case  XXXIV,  in  which  the  lesion  resembled 
coagulative  necrosis  of  the  liver,  were  from  necessity 
studied  less  completely  and  the  condition  of  the  islands 
was  not  so  definitely  determined. 

Cecil  has  found  lesions  of  the  islands  of  Langerhans 
in  seventy-nine  (88  per  cent.)  of  ninety  cases  of  diabetes; 
in  the  remaining  cases  the  pancreas  has  exhibited  no 
lesion,  and  it  is  doubtful  if  diabetes  has  been  referable 
to  this  organ.  In  forty-nine  cases  there  has  been  scle- 
rosis of  these  bodies ;  in  twenty-seven  instances,  hyaline 
degeneration,  often  combined  with  sclerosis;  in  one  in- 
stance, acute  inflammation  alone;  and  in  two  cases  of 
haemochromatosis,  deposit  of  iron-containing  pigment 
with  sclerosis.  In  four  instances  the  islands  of  Langer- 
hans were  sclerotic,  and  in  seven  instances  they  were 
the  seat  of  hyaline  degeneration,  although  the  secreting 
parenchyma  was  normal. 

Before  the  histological  studies  of  recent  years  no 
common  character  of  the  diverse  lesions  of  pancreatic 
diabetes  has  been  definable.  Destruction  of  parenchyma 
has  not  explained  the  occurrence  of  glycosuria,  for  lesions 


Fig.  46. — Advanced  hyaline  degeneration  of  islands  of  Langerhans;  secreting  parenchyma  nor- 
mal.    Photograpli  by  Dr.  Learning  from  Case  LXXI  (diabetes  mellitus)  of  Dr.  Cecil. 


PATHOLOGY  WITH  DIABETES  MELLITUS        327 

such  as  lithiasis  or  carcinoma,  which  cause  greatest 
destruction  of  parenchyma,  are  in  most  instances  unac- 
companied by  diabetes  mellitus.  When  the  various 
lesions  to  which  the  pancreas  is  subject  are  passed  in 
review,  it  is  found  that  changes  which  destroy  the  islands 
of  Langerhans,  especially  interacinar  pancreatitis  and 
hyaline  degeneration,  are  almost  constantly  accompanied 
by  diabetes,  whereas  those  lesions  which  destroy  the 
parenchyma  and  invade  the  islands  of  Langerhans  only 
when  the  change  is  far  advanced — namely,  interlobular 
pancreatitis,  lithiasis,  carcinoma — are  in  most  instances 
unaccompanied  by  diabetes.  Sauerbeck  has  been  able 
to  find  no  cases  in  which  severe  lesions  of  the  islands  of 
Langerhans  have  been  unaccompanied  by  diabetes, 
whereas  there  are  records  of  almost  innumerable  cases 
in  which  with  no  diabetes  the  islands  of  Langerhans  have 
been  normal,  although  the  secreting  parenchyma  has 
undergone  very  advanced  alteration  and  destruction. 

Lesions  of  the  pancreas  rarely  affect  the  islands  of 
Langerhans  and  leave  glandular  acini  unchanged,  yet  the 
careful  study  which  has  been  given  to  pancreatic  disease 
has  revealed  instances  in  which  with  diabetes  islands  of 
Langerhans  have  been  the  seat  of  destructive  lesions  (hya- 
line degeneration,  sclerosis),  whereas  the  secreting  pan- 
creas has  been  normal  (Fig.  46)  or  has  exhibited  trivial 
changes  not  infrequently  found  in  the  absence  of  dia- 
betes. Wright  and  Joslin,  Schmidt,  Herzog,  Miiller  and 
Norris  (see  Chap.  XTV)  have  found  the  islands  of  Lan- 
gerhans hyaline,  although  the  secreting  parenchyma  has 
been  normal;  in  a  similar  case  of  Eeitmann,  the  pancreas 
has  been  atrophic  in  appearance,  but  there  has  been  no 
increase  of  interstitial  tissue.     Among  ninety  cases  of 


328  DISEASE  OF  THE  PANCREAS 

diabetes  Cecil  found  hyaline  degeneration  of  the  islands 
of  Langerhans  unaccompanied  by  lesions  of  the  paren- 
chyma in  seven  instances.  (The  case  of  Norris  men- 
tioned above  is  included  in  this  series.)  Sclerosis  limited 
to  the  islands  of  Langerhans  and  accompanied  by  diabetes 
has  been  described  by  Schmidt  (with  foci  of  acute  in- 
flammation), Sauerbeck  and  Cecil  (see  Chap.  IX). 

Such  observations  have  almost  the  same  value  as  pur- 
posely performed  experiments,  for  in  the  absence  of  any 
evidence  that  these  changes  are  secondary  to  diabetes 
they  resemble  the  decisive  experiments  of  Von  Mering 
and  Minkowski  who,  it  is  well  known,  have  found  that 
extirpation  of  the  entire  gland  or  the  greater  part  of  the 
gland  is  followed  by  permanent  disturbance  of  carbo- 
hydrate metabolism. 

A  relation  between  lesions  of  the  islands  of  Langer- 
hans and  duration  of  diabetes  has  been  noted  by  Cecil. 
With  interacinar  pancreatitis  some  of  the  islands  of 
Langerhans  are  occasionally  surrounded  and  infiltrated 
with  lymphoid  cells;  the  presence  of  such  cells  indicates 
an  early  stage  in  the  development  of  the  lesion;  when 
sclerosis  is  advanced,  the  interacinar  islands  are  invaded 
by  fibrous  tissue  poor  in  cells.  In  a  few  instances  poly- 
nuclear  leucocytes  within  the  islands  of  Langerhans  show 
the  existence  of  acute  inflammation.  The  average  dura- 
tion of  diabetes  in  six  cases  in  which  the  islands  of 
Langerhans  are  infiltrated  with  cells  has  been  eleven 
months,  whereas  the  average  duration  in  forty-six  cases 
in  which  the  sclerotic  tissue  of  these  islands  is  poor  in 
cells  has  been  three  years  and  eleven  months.  In  sixteen 
cases  in  which  the  islands  of  Langerhans  are  the  seat  of 


PATHOLOGY  WITH  DIABETES  MELLITUS        329 

hyaline  degeneration  the  average  duration  of  diabetes  has 
been  three  years  and  six  months. 

The  following  grave  lesions  of  the  pancreas  have  been 
found  associated  with  diabetes  by  the  various  writers  who 
have  been  cited :  Carcinoma  destroying  the  gland ;  acute 
pancreatitis,  usually  with  hemorrhagic  necrosis  of  the 
organ ;  chronic  interstitial  pancreatitis  following  obstruc- 
tion of  the  ducts  by  calculi,  cysts,  or  carcinomata ;  chronic 
interstitial  pancreatitis  due  to  other  causes;  simple 
atrophy  of  the  pancreas.  Certain  features  associated 
with  each  of  these  conditions  demand  consideration,  but 
it  is  unnecessary  to  discuss  the  relationship  to  diabetes 
of  less  important  alterations,  for  example,  hyperjemia, 
parenchymatous  and  fatty  degeneration,  which  commonly 
occur  without  any  disturbance  of  carbohydrate  metab- 
olism. 

Destructive  Lesions  of  the  Pancreas  with  Diabetes. — 
Though  complete  removal  of  the  pancreas  in  lower  ani- 
mals is  followed  by  diabetes,  numerous  writers  have 
claimed  that  complete  destruction  of  the  organ,  by  hemor- 
rhagic necrosis,  hemorrhagic  inflammation,  or  by  car- 
cinoma invading  and  destroying  the  gland,  is  not  in- 
variably followed  by  diabetes. 

Acute  lesions  of  the  pancreas  associated  with  suppura- 
tion or  necrosis  may  cause  extensive  destruction  of  the 
gland,  yet  in  only  six  of  one  hundred  and  five  cases  col- 
lected by  Egdahl  ^'^  was  sugar  present  in  the  urine.  De- 
struction of  the  pancreas  by  hemorrhagic  necrosis  is 
rarely  complete,  and  in  most  instances  enough  paren- 
chyma remains  to  prevent  onset  of  glycosuria.     After 

'^*  Loc.  cit.,  p.  135. 


330  DISEASE  OF  THE  PANCREAS 

extirpation  of  the  pancreas  in  animals  a  variable  time 
elapses  before  sugar  appears  in  the  urine;  and  in  most 
cases,  shortly  before  the  fatal  termination  or  with  the 
onset  of  severe  complications,  glycosuria  disappears. 
With  rapidly  fatal  lesions  death  may  occur  before  onset 
of  glycosuria. 

Destruction  of  the  pancreas  may  be  caused  by  diffuse 
carcinomatous  new  growth  invading  the  organ  and  re- 
placing the  parenchyma.  In  another  category  belong 
those  more  frequent  instances  in  which  a  new  growth 
compressing  the  duct  has  produced  secondary  chronic 
inflammation  of  the  gland.  Hansemann  described  two 
cases  in  which  a  diffuse  primary  carcinoma  of  the  pan- 
creas had  apparently  caused  complete  destruction  of  the 
organ;  nevertheless,  diabetes  was  absent.  He  has  sug- 
gested that  the  tumor  cells  derived  from  the  parenchyma 
of  the  gland  are  capable  of  exerting  that  influence  upon 
carbohydrate  metabolism  which  is  attributed  to  the  nor- 
mal gland. 

The  difficulty  of  identifying  within  a  carcinomatous 
mass  small  indurated,  but  yet  well  preserved,  areas  of 
pancreatic  parenchyma  is  considerable ;  and  even  though 
the  secreting  acini  have  been  destroyed,  islands  of  Lan- 
gerhans,  which  superficially  resemble  alveoli  of  carcino- 
matous cells,  may  still  persist.  Pearce  ^^  has  demon- 
strated that  islands  of  Langerhans  may  survive  although 
the  surrounding  parenchyma  has  been  destroyed  by  can- 
cer. At  the  margin  of  the  advancing  tumors  islands  of 
Langerhans  may  persist  enclosed  within  masses  of  tumor 
cells.  Those  islands  of  Langerhans  which  are  isolated 
in  the  stroma  may  undergo  hypertrophy  so  that  they  be- 

"  Loe.  cit. 


PATHOLOGY  WITH  DIABETES  MELLITUS        331 

come  four  or  five  times  their  normal  size.  The  resisting 
islands  of  Langerhans  may  be  finally  destroyed  by  en- 
croachment of  the  sclerotic  stroma. 

Chronic  Interstitial  Pancreatitis  ivith  Diabetes. — The 
association  of  chronic  interstitial  inflammation  with  dia- 
betes is  demonstrated  by  the  foregoing  tables.  Chronic 
interlobular  pancreatitis  follows  obstruction  of  the  pan- 
creatic duct  by  calculi,  by  carcinoma  of  the  head  of  the 
gland,  or  by  cysts  causing  compression  of  the  ducts, 
and  such  lesions  are  cited  in  the  statistics  of  Hanse- 
mann  (twenty-one  of  seventy-two  cases)  and  of  Oser  (fifty- 
seven  of  one  hundred  and  eighty-eight  cases).  Though  a 
lar'ge  number  of  such  cases  have  been  recorded  they 
are  much  less  frequent  than  these  figures  indicate.  When 
consecutive  cases  of  diabetes  have  been  studied  duct- 
obstruction  in  association  with  diabetes  is  uncommon, 
lithiasis,  cyst,  and  carcinoma  being  represented  by  only 
fifteen  among  two  hundred  and  eighty-eight  cases  col- 
lected by  Sauerbeck  from  recent  literature  of  the  subject. 
In  none  of  forty  cases  observed  by  Hansemann  did  he 
find  sclerosis  consequent  upon  the  presence  of  calculi, 
but  in  two  examples  of  advanced  scleroses  with  calculi 
diabetes  was  absent. 

In  only  one  of  the  cases  which  I  have  described  did 
diabetes  accompany  pancreatic  calculi;  here  the  conse- 
quent interlobular  inflammation  of  the  gland  and  de- 
struction of  its  parenchyma  was  far  advanced  and  the 
islands  of  Langerhans  were  implicated.  Of  considerable 
importance  is  the  fact  that  the  associated  diabetes  was 
of  mild  character,  glycosuria  disappearing  when  carbo- 
hydrates were  withdrawn  from  the  diet.  On  the  other 
hand,  in  two  of  my  cases  with  advanced  sclerosis  follow- 
ing obstruction  of  the  pancreatic  duct — in  one  case  caused 


332  DISEASE  OF  THE  PANCREAS 

by  calculi  (Case  XXVI),  in  another  by  carcinoma  (Case 
XII) — diabetes  was  absent  and  the  islands  of  Langer- 
hans  were  intact.  In  two  cases  of  pancreatic  lithiasis 
accompanied  by  diabetes,  Lazarus  ^^  found  both  acini  and 
islands  of  Langerhans  destroyed,  but  in  a  similar  case 
without  diabetes  chronic  pancreatitis  was  less  advanced 
and  numerous  unaltered  islands  of  Langerhans  persisted 
although  surrounding  acini  had  been  destroyed.  Liga- 
tion of  the  pancreatic  ducts  in  animals  is  followed  by 
chronic  interlobular  inflammation,  which  for  a  long  time 
spares  the  islands  of  Langerhans,  and  the  lesion  rarely, 
if  ever,  reaches  such  an  advanced  stage  that  diabetes 
ensues.  The  inflammatory  changes  which  in  human  be- 
ings follow  duct-obstruction  are  especially  severe  because 
they  are  associated  in  most  instances  with  conditions 
favoring  ascending  infection  with  bacteria,  but  they  are 
followed  by  diabetes  only  when  they  have  reached  such 
an  advanced  stage  that  the  parenchyma  is  almost  wholly 
replaced  and  compressed  by  dense  fibrous  tissue. 

Chronic  i3ancreatitis  due  to  causes  other  than  duct- 
obstruction  is  not  infrequently  associated  with  diabetes, 
but  chronic  pancreatitis  is  not  always,  or  indeed  in  the 
majority  of  instances,  accompanied  by  diabetes.  To  pro- 
duce diabetes  mellitus  in  animals  it  is  necessary  to  re- 
move a  considerable  part  of  the  pancreas;  a  case  pre- 
viously cited  (page  110)  shows  that  removal  of  two-thirds 
of  the  human  pancreas  may  cause  glycosuria.  Diabetes 
mellitus  accompanies  chronic  inflammation  of  the  pan- 
creas only  when  a  considerable  part  of  the  parenchyma 
has  been  destroyed  or  functionally  impaired. 

"Loc.  cit.,  p.  257. 


PATHOLOGY  WITH  DIABETES  MELLITUS        333 

Various  observers  have  attempted  to  define  a  type  of 
pancreatitis  peculiar  to  diabetes.  G.  Hoppe-Seyler  ^^ 
and  Fleiner  ^^  have  described  instances  of  the  disease 
in  which  chronic  in4;erstitial  inflammation  of  the  pan- 
creas accompanied  general  arterial  sclerosis.  Lemoine 
and  Lannois,''^  as  already  noted,  have  studied  pancreatitis 
in  four  cases  of  diabetes,  and  have  thought  that  the  new 
growth  of  interstitial  tissue  has  its  seat  of  origin  in  the 
perivascular  tissue,  whence  fibrous  processes  extend  be- 
tween the  parenchymatous  structures  and  even  into  the 
acini,  separating  the  cells  and  producing  what  they  desig- 
nate unicellular  sclerosis. 

Hansemann  has  claimed  that  one  variety  of  pancrea- 
titis is  always  accompanied  by  diabetes.  He  designates 
the  condition  atrophy,  but  the  character  of  the  lesion 
and,  what  he  particularly  emphasizes,  the  features  which 
distinguish  it  from  atrophy  consequent  upon  emaciation 
identify  it  as  chronic  inflammation.  The  organ  is  dimin- 
ished in  size,  flattened  and  unusually  adherent  to  neigh- 
boring structures;  the  microscope  demonstrates  an 
atrophy  of  the  parenchymatous  elements,  which  are  in 
part  replaced  by  new  fibrous  tissue.  With  cachectic 
atrophy,  on  the  contrary,  glandular  cells  and  interstitial 
tissue  have  undergone  equal  atrophy.  Hansemann  thinks 
that  this  pancreatic  lesion  characteristic  of  diabetes  is 
similar  to  certain  forms  of  granular  atrophy  of  the  kid- 
neys. Since  the  new  growth  of  interstitial  tissue  never 
reaches  such  extent  that  the  organ  is  increased  in  size,  he 
distinguishes  granular  atrophy  from  fibrous  induration 
with   hypertrophy,   which   in   three   instances  he  found 

"  Loc.  cit.,  Chap.  IX. 


334>  DISEASE  OF  THE  PANCREAS 

associated  with  diabetes.  This  fibrous  induration  char- 
acterized by  coarse  bands  of  newly-formed  stroma  is  not 
unconnnon,  but  is  usually  unaccompanied  by  diabetes. 

Comparison  of  the  series  of  cases  recorded  by  Hanse- 
mann  in  1894  with  those  subsequently  studied  by  histo- 
logical methods  shows  that  the  so-called  granular  atrophy 
which  he  found  peculiar  to  diabetes  mellitus  corresponds 
in  frequency  with  the  interacinar  pancreatitis  or  fine 
sclerosis  which  has  been  present  in  a  large  proportion 
of  more  recently  recorded  cases.  With  this  lesion  the 
islands  of  Langerhans  are  implicated;  they  are  invaded 
by  newly-formed  fibrous  tissue,  and  are  not  infrequently 
the  site  of  hyaline  degeneration.  Among  sixty-three  in- 
stances of  interacinar  pancreatitis  occurring  in  ninety 
diabetics  studied  by  Cecil,  the  islands  of  Langerhans  have 
exhibited  sclerosis  in  forty-one,  hyaline  degeneration  in 
twenty,  and  deposit  of  haemosiderin  (haBmochromatosis) 
in  two. 

The  lesion  which  Hansemann  designated  fibrous  in- 
duration with  hypertrophy  is  doubtless  identical  with 
chronic  interlobular  pancreatitis;  it  has  occurred  only 
three  times  among  thirty- seven  cases  of  Hansemann  and 
only  four  times  among  ninety  cases  of  Cecil. 

Simple  Atrophy  of  the  Pancreas  with  Diabetes  Mel- 
litus.— Diminution  in  the  size  of  the  pancreas  with  or 
without  structural  changes  has  been  more  frequently 
noted  in  association  with  diabetes  than  any  other  abnor- 
mality. The  normal  organ  is  subject  to  much  variation 
and  its  weight  is  diiferently  estimated  by  anatomists. 
Vierordt  ^^  has  found  the  average  normal  weight  97.6 

'*'Vierordt:  Anat.,  physiol.  luul  physikal.  Daten  und  Tabellen, 
Jena.  1906. 


PATHOLOGY  WITH  DIABETES  MELLITUS        335 

Gm.  Krause  ^^  found  the  weight  from  66  to  102  Gm. 
Doubtless  a  weight  below  65  Gm.  should  be  regarded  as 
abnormal.  So-called  atrophy  has  been  frequently  asso- 
ciated with  severe  alterations  of  the  parenchyma,  notably 
with  chronic  interstitial  inflammation,  and  such  cases 
should  be  separated  from  those  in  which  the  tissue  pre- 
sents a  normal  histological  character. 

Hansemann  discusses  the  relationship  of  simple 
atrophy  to  diabetes.  Is  it  a  consequence  of  the  general 
emaciation  associated  with  diabetes,  and  is  it  therefore 
secondary  to  this  disease?  The  pancreas  doubtless 
shares  the  atrophy  which  all  organs  undergo  as  the  result 
of  cachexia  from  any  cause;  but  since  he  has  found  the 
pancreas  little  affected  when  the  other  organs  of  an 
emaciated  individual  are  much  diminished  in  weight, 
Hansemann  concludes  that  only  a  slight  diminution  in 
size  can  be  secondary  to  diabetes.  Moreover,  atrophy  of 
the  pancreas  is  not  limited  to  cases  of  diabetes  accom- 
panied by  emaciation,  for  Hansemann  found  that  of 
thirty-six  cases  in  which  the  pancreas  was  atrophied,  in 
six  instances  the  affected  individual  was  corpulent. 
Moreover,  the  characters  of  so-called  granular  atrophy  of 
diabetes  defined  by  Hansemann  remove  it  from  the  do- 
main of  simple  atrophy  and  characterize  it  as  chronic 
inflammation. 

Ssobolew,''°Weiehselbaum  and  Stangl,"^  andReitmann''  havedeseribed 
groups  of  eases  at  variance  with  those  previously  cited  (page  321),  for 
they  contain  few,  if  any,  examples  of  interacinar  pancreatitis.  In 
these  three  series  of  eases  the  lesion  most  frequentlj'^  observed  with 

"  Krause :  Handb.  der  mench.  Anat,,  vol.  ii,  1879. 
^*  Ssobolew :  Virchow's  Arch.,  1902,  elxviii,  91. 
"  Log.  cit. 


336  DISEASE  OF  THE  PANCREAS 

diabetes  is  designated  simple  ati'ophy;  Ssobolew  found  simple  atrophy 
in  fourteen  of  fifteen  cases  of  diabetes,  and  Weichselbaiun  and  Stangl 
found  so-called  simple  atrophy  in  twenty-three  of  thirty-five  cases  of 
diabetes.  Ssobolew  has  found  the  islands  of  Langerhans  of  the  atrophic 
pancreas  constantly  diminished  in  number,  and  Weichselbaimi  and 
Stangl  have  found  various  degenerative  changes — namely,  diminution 
in  size  of  the  cells,  vacuolization,  and  pyknosis  of  nuclei.  Since  the 
last-named  observers  found  in  some  of  their  cases  increase  of  connec- 
tive tissue  within  and  about  the  islands  of  Langerhans,  and  in  some 
instances  hyaline  degeneration,  it  is  probable  that  so-called  simple 
atrophy  described  by  them  is  identical  in  part  at  least  with  what  the 
greater  number  of  writers  have  described  as  interacinar  pancreatitis 
(or  fine  sclerosis).  The  series  of  cases  described  by  Reitmann  is 
equally  anomalous,  for  among  seventeen  cases  of  diabetes  he  found 
interacinar  pancreatitis  in  only  one  case,  whereas  this  lesion  has 
occurred  one  hundred  and  twenty-three  times  among  two  hundred  and 
eighty-eight  cases  of  diabetes  collected  from  the  literature  of  the  sub- 
ject. Reitmann  has  found  in  seven  cases  simple  atrophy  characterized 
by  degenerative  changes  in  the  secreting  parenchyma;  in  places  the 
glandular  cells  lose  their  zymogen  granules  and  become  vacuolated, 
while  elsewhere  in  the  parenchyma  regenerative  changes  occur.  Such 
degenerative  and  regenerative  changes  are,  Reitmann  claims,  an  exag- 
geration of  processes  which  occur  under  normal  conditions  and  have 
been  demonstrable  in  the  panci'eas  of  criminals  immediately  after 
execution.  When  degenerative  changes  are  active  glandular  paren- 
chyma is  replaced  by  fat;  thei*e  may  be  increase  of  connective  tissue, 
so  that  in  certain  stages,  according  to  Reitmann,  the  lesion  resembles 
what  Hansemann  has  described  as  granular  atrophy. 

The  foregoing  considerations  show  that  the  change 
which  has  been  designated  simple  atrophy  by  Ssobolew, 
Weichselbaum  and  Stangl  and  Reitman  is  a  chronic  in- 
flammatory process  which  has  been  described  by  other 
writers  as  interacinar  pancreatitis,  fine  sclerosis,  or 
granular  atrophy. 


PATHOLOGY  WITH  DIABETES  MELLITUS        337 

Abnormally  Small  Pancreas  ivith  Diabetes. — The  pan- 
creas of  diabetics  is  not  infrequently  described  as 
atrophic  merely  because  it  is  small.  The  parenchy- 
matous cells  may  exhibit  no  appearance  of  atrophy,  and 
there  may  be  no  evidence  that  the  organ  has  undergone 
changes  which  have  reduced  its  size.  The  gland  in  some 
individuals  is  far  below  the  average  size,  and  it  is  pos- 
sible that  such  individuals  are  especially  susceptible  to 
diabetes  mellitus. 

In  a  carefully  studied  series  of  cases  Williamson  ^^ 
has  demonstrated  the  coexistence  of  diabetes  and  extreme 
diminution  in  the  size  of  the  pancreas  unassociated  with 
any  demonstrable  alteration  of  the  parenchyma.  In 
three  of  twenty-three  cases  the  pancreas  was  atrophied 
to  an  extent  bearing  no  relationship  to  the  general  wast- 
ing of  the  other  organs,  and  the  parenchyma  appeared 
to  be  normal.  In  one  instance  the  organ  in  a  man  forty- 
six  years  of  age  weighed  only  a  quarter  of  an  ounce  (8 
Gm.). 

In  three  of  my  cases  the  pancreas  was  diminished  in 
size  (three  glands  weighing  60,  58,  and  51  Grm.  in  individ- 
uals respectively  forty-six,  fifty-six,  and  thirty  years  of 
age,  but  no  other  alterations  were  observable.  In  four 
of  twenty- two  cases  of  diabetes  described  by  W.  Miiller  ^^ 
the  pancreas,  which  was  wholly  normal  in  structure,  was 
unusually  small.  When  the  gland  shows  no  structural 
change,  it  is  probable  that  the  condition  is  congenital, 
and  the  pancreas  being  unusually  small,  at  some  period 
of  life  fails  to  meet  the  demand  made  upon  it,  so  that 

^  Williamson :  Diabetes  Mellitus.     Edinburgh  and  London,  1898. 
^Miiller:  Inaug.  Diss.,  Berlin,  1905. 


338  DISEASE  OF  THE  PANCREAS 

diabetes  results.  Diminution  in  tlie  size  of  the  pancreas 
is  presumably  accompanied  by  diminution  in  the  number 
of  islands  of  Langerhans. 

Relation  of  Diabetes  to  a  Diminution  in  the  Number 
of  Islands  of  Langerhans. — Several  writers  have  claimed 
that  diabetes  may  be  associated  with  diminution  or  even 
entire  absence  of  the  islands  of  Langerhans.  Ssobolew  ^^ 
in  a  preliminary  communication  published  in  1900  cited 
two  cases  of  diabetes  in  which,  he  claimed,  these  struc- 
tures were  wholly  absent,  and  in  four  of  fifteen  cases  de- 
scribed several  years  later  he  failed  to  find  them.  Since 
the  secreting  parenchyma  was  entirely  normal,  he 
assumed  that  the  interacinar  islands  might  disappear 
without  leaving  any  trace.  In  nine  cases  he  found  the 
number  of  islands  of  Langerhans  diminished.  Schmidt 
has  never  failed  to  find  interacinar  islands  and  is  skepti- 
cal of  Ssobolew 's  observations.  Ssobolew  did  not  exam- 
ine sections  from  the  various  parts  of  the  pancreas  and 
failed  to  recognize  the  truth  that  islands  of  Langerhans 
may  be  very  numerous  in  the  tail  of  the  gland  while  they 
may  be  almost  absent  from  other  parts.  In  single  sec- 
tions I  have  failed  to  discover  these  structures,  but  in 
all  cases  of  diabetes  which  I  have  examined,  and  in  all  of 
ninety  cases  examined  by  Cecil,  they  have  been  found  in 
fair  abundance,  particularly  in  the  tail  of  the  organ. 

Weichselbaum  and  Stangl  compared  sections  from  the 
pancreas  of  diabetics  with  control  specimens  made  from 
corresponding  parts  of  the  pancreas  obtained  from  in- 
dividuals of  the  same  age,  and  reached  the  conclusion 
that  the  number  of  islands  of  Langerhans  may  be  dimin- 

"  Ssobolew :  Cent,  f .  allg.  Path.  u.  path.  Anat.,  1900,  xi,  202. 


PATHOLOGY  WITH  DIABETES  MELLITUS 


ished  with  diabetes;  and  since  the  pancreas  is  almost 
constantly  small,  the  total  number  of  islands  is  still  less 
than  normal.  They  do  not,  however,  separate  cases  in 
which  the  islands  of  Langerhans  showed  lesions  from 
.  those  in  which  they  were  apparently  normal. 

In  order  to  determine  definitely  the  number  of  the 
islands  of  Langerhans  it  is  essential  to  estimate  their 
number  in  section  from  corresponding  parts  of  the  gland. 
When  the  inter  acinar  bodies  are  the  seat  of  destructive 
lesions  it  is  obvious  that  the  number  capable  of  fune 
tional  activity  is  diminished,  but  considerable  interest 
attaches  to  those  cases  in  which  no  lesion  can  be  demon- 
strated. 

In  the  following  eases  of  this  character  sections  from  three  parts 
of  the  gland  were  examined  (exceptions  are  noted)  and  the  numbei 
of  islands  of  Langerhans  in  0.5  square  centimetre  determined. 


Nc^of  case. 

Age  of  patient 
in  years. 

Weight  of 
pancreas  in 
grammes. 

Relative  niimber  of  islands  of  Langerhans  in 

Head. 

Body. 

Tail. 

I 

II 

III 

IV 

fVI 
VII 

33 
46 
56 
14 
10 
30 

60 

58 

45 
51 
54.5 

..    (9) 
..(23) 
17 
12 
50 
6 
32 

..      (5) 
..     (21) 
16 

5 
19 

5 
31 

32 

10         i 

42 

8 
42 

Note. — In  Cases  I  and  II  tissue  was  not-  preserved  from  different  parte 
of  the  gland  and  the  figures  in  parenthesis  represent  the  number  of  interacinar 
islands  in  sections  taken  at  random.  > 


Comparison  with  the  table  on  page  62  shows  that  the  above 
figures  present  no  constant  departure  from  the  normal.  In  the  head 
and  body  about  eighteen  islands  occur  in  0.5  square  centimetres;  in 
the  tail,  approximately  thirty-two.  A  striking  diminution  is  seen  in 
Cases  IV   and   VI,   and   is   particularly   noteworthy   in    Case   IV,    a 


540  DISEASE  OF  THE  PANCREAS 

child  of  fourteen  years,  ia  whose  pancreas  we  would  expect  the  num- 
ber of  islands  to  be  greater  than  in  that  of  the  adult.  In  this  case! 
the  existence  of  hereditary  diabetes  ^  suggests  the  occurrence  of  a  con- 
genital defect  of  the  gland.  In  no  instance  does  the  appearance  of  the 
gland  suggest  a  condition  of  atrophy. 

The  islands  of  Langerhans  were  counted  by  Sauerbeck^  in  the 
pancreas  of  thirteen  individuals  who  had  suffered  with  diabetes;  in  all 
but  one  instance  the  number  was  less  than  that  found  in  any  one  of 
several  normal  glands  (from  2 J  to  9 J  within  an  area  approximately 
4  square  millimetres).  In  three  eases  of  diabetes  the  pancreas  was 
normal  or  exhibited  "atrophy";  the  figures  obtained  were:  (1),  3.4 
(aged  84  years)  ;  (II),  1.1  (aged  26  years) ;  (III),  O.G  (aged  29  yeais; 
"atrophic  pancreas").  In  one  of  these  instances  (I)  the  number  was 
within  tlie  lower  limit  of  the  nonual,  whereas  in  two  instances  the 
number  was  considerably  less  than  normal. 

Miiller  has  counted  the  islands  of  Langerhans  in  a  given  area  of 
parenchyma,  and  when  the  gland  has  been  unusually  small  has  roughly 
estimated  the  relation  between  the  mass  of  the  gland  and  the  absolute 
number  of  the  islands  of  Langerhans.  In  three  instances  in  which 
the  gland  has  shown  no  lesion  he  has  found  that  the  number  of  inter- 
acinar  bodies  has  been  unusually  small ;  in  a  pancreas  weighing  46  Gm. 
from  a  man  aged  twenty-one  years  the  islands  of  Langerhans  thus 
estimated  have  been  one-twelfth  as  abundant  as  in  the  normal  pancreas. 

Glycosuria  may  follow  the  partial  removal  of  the 
human  pancreas,  even  though  one-third  of  the  gland  re- 
main (see  Chap.  V).  Nevertheless,  a  gland  weighing 
from  50  to  60  Gm.,  even  should  the  relative  number  of 
islands  be  small,  might  be  sufficient  to  prevent  diabetes. 
We  are,  however,  unable  to  estimate  the  effect  of  pro- 
longed exertion  on  the  part  of  the  defective  gland  to 

"  The  case  is  described  by  Dr.  Pleasants  in  a  paper  on  "  Heredity 
in  Diabetes  Mellitus  with  a  Report  of  Six  Cases  Occurring  in  a 
Family."     Bulletin  of  the  Johns  Hopkins  Hospital,  1900,  xi,  325. 

"  Sauerbeck :  Virchow's  Arch.,  1904,  Suppl.  to  clxxvii,  1. 


PATHOLOGY  WITH  DIABETES  MELLITUS        341 

carry  on  functions  necessary  to  noimal  metabolism. 
Moreover,  slight,  hardly  recognizable  changes — for  ex- 
ample, arterial  sclerosis — may  at  some  period  of  life  be 
suflScient  to  overtopple  the  equilibrium  heretofore  pre- 
served by  the  overworked  gland. 

Hypertrophy  of  the  Islcmds  of  Langerhans  with  Dia- 
betes.— Hypertrophy  of  the  islands  of  Langerhans  has 
been  observed  in  association  with  lesions  which  destroy 
or  injure  some  of  these  bodies  and  presumably  force  to 
unusual  functional  activity  those  which  remain.  In  the 
absence  of  diabetes  mellitus,  Pearce  ^^  has  found  the 
islands  of  Langerhans  unusually  enlarged  along  the  ad- 
vancing edge  of  a  malignant  growth.  Though  these 
structures  survive  the  secreting  parenchyma,  and  persist 
occasionally  within  a  mass  of  tumor  cells,  some  of  them 
are  finally  destroyed;  a  part  of  those  which  remain  are 
four  or  five  times  the  size  of  normal  islands  of  Langer- 
hans. Ohlmacher  ^  has  observed  cirrhosis  of  the  liver 
accompanied  by  hyaline  degeneration  affecting  some  of 
the  islands  of  Langerhans;  he  attributes  absence  of 
glycosuria  to  the  great  hypertrophy  exhibited  by  those 
islands  which  have  been  uninjured.  To  what  extent  such 
hypertrophied  islands  of  Langerhans  are  capable  of 
vicariously  assuming  the  function  of  those  which  have 
been  destroyed,  it  is  impossible  to  decide.  Similar  hyper- 
trophy has  been  observed  repeatedly  in  association  with 
diabetes  mellitus,  and  has  been  found  with  interacinar 
pancreatitis  when  neighboring  islands  have  been  the  seat 
of  sclerosis  and  hyaline  degeneration  (Fig.  47).    (Pearce, 


"  Loc.  cit.,  p.  291. 

''  OUmaeher :  American  Jour,  of  the  Med.  Seieu.,  1904,  cxxviii,  287. 


S42  DISEASE  OF  THE  PANCREAS 

Gurtis  and  Gelle,2^  Herxheimer  "^  and  Miiller.)  In  more 
than  a  third  of  ninety  cases  of  diabetes  Cecil  found  hyper- 
trophy of  the  islands  of  Langerhans. 

The  interacinar  islands  which  have  undergone  the 
enlargement  just  described  preserve  their  usual  structure 
(Fig.  47),  but  with  a  second  type  of  hypertrophy  which 
lias  been  observed  with  diabetes  mellitus  the  cells  and 
their  arrangement  are  altered  (Fig.  48).  Eeitmann  ^^  de- 
scribed the  pancreas  of  a  man  sixty-two  years  of  age, 
whose  urine  had  shown  slight  reduction  when  tested 
for  sugar  by  Nylander's  method;  there  was  some  in- 
crease of  the  interlobular  connective  tissue,  and  the  ducts 
of  the  gland  were  acutely  inflamed.  The  greater  number 
of  the  islands  of  Langerhans  were  normal,  but  limited 
to  the  mid-part  of  the  head  of  the  pancreas,  and  often 
constituting  the  chief  part  of  a  lobule,  were  areas  in 
which  high  cylindrical  cells  were  arranged  like  those  of 
the  islands  of  Langerhans.  The  capillaries  between 
these  cell-columns  were  not  so  wide  nor  so  numerous  as 
those  of  the  normal  interacinar  islands,  and  more  closely 
resembled  the  capillaries  about  the  acini.  Ssobolew  ^- 
has  designated  a  similar  change,  ''struma"  of  the  islands 
of  Langerhans.  In  the  pancreas  of  a  diabetic  woman, 
aged  fifty-five  years,  he  found  a  body  1.5  mm.  in  diame- 
ter composed  of  cylindrical  cells  with  centrally  placed 
nuclei.  Some  smaller  islands  of  Langerhans  had  similar 
character,  whereas  other  interacinar  islands  were  hyaline 


Curtis  and  Gelle :    Compt.  rend.  Soc.  de  bioL,  1905,  i,  942,  943. 
Herxheiraer:  Verhandl.  d.  deutsehe  path.  Gesell.,  1905,  ix,  263. 
hoc.  cit. 
Ssobolew:  Virchow's  Arch.,  1904,  Suppl.  to  clxxvii,  123. 


Fig.  47. — Hypertrophy  of  island  of  Langerlians  (at  top  of  figure)  in  association  witli  liyaline 
degeneration  of  islands  of  lyangerhans.  Photograph  by  Dr.  Learning  from  Case  XXXVII  (dia- 
betes mellitus)  of  Dr.  Cecil. 


Fig.  48. — ^Adeiioiiia-like  hypertrophy  of  island  of  l.angerhans  showing  cells  which  have 
assumed  a  columnar  form,  and  nuclei  situated  in  the  mid-part  of  tlie  cells.  Photograph 'of  Dr. 
Leaming  from  Case  XXIX  (diahotes  mellilus)  of  Dr.  (Veil. 


PATHOLOGY  WITH  DIABETES  MELLITUS        343 

and  sclerotic;  the  interstitial  tissue  of  the  gland  was 
increased. 

In  two  cases  of  diabetes  described  by  Karakascheff  ^' 
cell-columns  of  enlarged  islands  of  Langerhans  were 
formed  by  cylindrical  cells;  such  islands  had  no  well- 
defined  capsule  and  the  cell-columns,  it  was  believed,  were 
continuous  with  neighboring  acini.  The  condition 
occurred  in  individuals  aged  respectively  sixteen  and 
twenty-one  years.  Herxheimer  ^^  found  the  same  change 
in  two  cases  of  diabetes,  in  both  instances  associated  with 
interacinar  pancreatitis,  sclerosis,  and  hyaline  degenera- 
tion of  islands  of  Langerhans. 

In  the  pancreas,  from  a  diabetic  boy  ten  years  of  age, 
MacCallum^^  found  enlarged  islands  of  'Langerhan's' 
which  were  not  sharply  outlined  because  the  strands  of 
cells  which  composed  them  were  apparently  continuous 
with  adjacent  acini.  Such  strands  were  composed  of  a 
single  row  of  elongated  cells  with  square  ends ;  the  nuclei, 
which  were  large  and  stained  deeply,  occupied  the  centre 
of  the  cell  and  hence  formed  a  line  along  the  middle  of 
each  column  of  cells.  About  the  hypertrophied  islands  of 
Langerhans  acini  and  the  cells  composing  them  were 
unusually  large.  In  a  second  child  with  diabetes,  a  boy 
aged  ten  years,  there  were  changes  identical  with  those 
just  described. 

This  peculiar  change,  which  has  been  designated 
adenoma-like  hypertrophy,  has  been  present  in  seven  of 

^  Karakascheff :  Deutsches  Arch.  f.  klin.  Med.,  1905,  Ixxxii,  60; 
1906,  Ixxxvii,  291. 

^  Herxheimer :  Loc.  cit. 

"MacCallum:  American  Jour,  of  the  Med.  Scien.,  1907,  cxxxiii, 
432. 


344  DISEASE  OF  THE  PANCREAS 

ninety  diabetics  examined  by  Cecil.  In  five  instances 
in  individuals  aged  from  thirty-one  to  seventy-five  years 
it  lias  accompanied  interacinar  pancreatitis,  but  in  two 
instances  in  individuals  aged  respectively  twenty  and 
thirty-one  years  the  secreting  parenchyma  has  been  nor- 
mal, though  some  of  the  islands  of  Langerhans  have  ex- 
hibited acute  or  chronic  inflammatory  changes.  Weich- 
selbaum  ^'^  has  repeatedly  observed  this  condition  of  the 
islands  of  Langerhans  with  diabetes  and  believes  that  it 
represents  regeneration  of  islands  of  Langerhans.  He 
thinks  that  such  regeneration  occurs  by  development  of 
solid  cellular  outgrowths  from  the  ducts  of  the  gland, 
for  he  has  frequently  found  columns  of  high  cylindrical 
cells  grouped  about  a  small  duct,  with  which  they  are 
continuous. 

It  is  not  improbable  that  an  adenoma-like  type  of 
hypertrophy  occurs  under  conditions  which  are  obscure, 
in  response  to  an  unusual  demand  upon  the  islands  of 
Langerhans,  and  represents  an  attempt  to  overcome  func- 
tional insufficiency  of  these  bodies.  This  form  of  hyper- 
trophy occurs  in  young  individuals,  and  may  be  unasso- 
ciated  with  inflammation  of  the  parenchyma;  in  older 
individuals,  it  accompanies  interacinar  pancreatitis.  The 
change  has  been  found  only  in  association  with 
glycosuria. 

Experimental  Study  of  the  Relation  of  Islands  of 
Langerhans  to  Diabetes. — Experiments  on  animals  have 
given  confirmation  to  the  view  that  islands  of  Langer- 
hans control  carbohydrate  metabolism.     It  has  long  been 

"  Weichselbaum :  Sitz.  d.  k.  Akad.  d.  Wsch.  Math.-nat.  KL,  1908. 
Ref.,  Cent.  f.  allg.  Path.  u.  path.  Anat.,  1909,  xx,  184. 


PATHOLOGY  WITH  DIABETES  MELLITUS        345 

known  that  ligation  of  the  pancreatic  ducts,  and  conse- 
quent chronic  interstitial  inflammation  is  not  accompan- 
ied by  diabetes ;  Schultze  ^'^.  has  found  that  inflammatory 
atrophy  of  the  pancreas,  caused  by  a  ligature  tied  tightly 
about  the  gland  of  guinea-pigs,  spares  the  islands  of 
Langerhans,  which  persist  unaltered  in  the  newly-formed 
stroma.  Ssobolew  ^^  has  studied  the  changes  which  fol- 
low ligation  of  the  pancreatic  ducts  in  rabbits.  Fifteen 
days  after  operation  secreting  acini  have  disappeared  in 
many  lobules,  but  in  a  few  lobules  acini  may  be  present 
at  the  end  of  thirty  days.  Islands  of  Langerhans  remain 
almost  wholly  unaltered  though  surrounded  by  the  newly- 
formed  connective  tissue  which  has  replaced  the  acini. 
They  persist  at  the  end  of  four  hundred  days  at  a  time 
when  smaller  ducts  have  disappeared  and  the  chief  pan- 
creatic duct  alone  represents  the  secreting  apparatus  of 
the  gland;  nevertheless,  there  is  no  diabetes.  Ssobolew 
found  that  some  islands  of  Langerhans  are  compressed 
and  destroyed  by  newly-formed  stroma  during  the  period 
from  thirty  to  one  hundred  and  twenty  days  after  opera- 
tion. Sauerbeck  ^^  has  confirmed  this  observation,  and 
in  four  animals  examined  within  this  period  has  found 
glycosuria  and  insular  changes.  Hypertrophy  of  islands 
of  Langerhans,  noted  by  Weichselbaum,  may  explain  dis- 
appearance of  glycosuria  at  a  later  period. 

Ssobolew  has  found  that  islands  of  Langerhans  of 
the  dog  persist  when  a  part  of  the  pancreas  is  trans- 
planted into  the  abdominal  wall;  fifty  days  after  opera- 
tion lobules  of  the  gland  are  atrophied,  but  islands  of 

^^  Loe.  cit.,  p.  217. 
'"Loc.  cit.,  p.  217. 


346  DISEASE  OF  THE  PANCREAS 

Langerhans  are  well  preserved.  In  an  animal  killed  one 
hundred  and  tliirty  days  after  operation,  the  tissue  which 
has  remained  has  contained  ducts  and  a  small  number  of 
islands  of  Langerhans.  MacCallum^^  has  placed  two 
ligatures  about  the  pancreas  of  a  dog  and  has  separated 
this  part  from  the  remainder  by  a  cut  between  the  liga- 
tures. Atrophy  of  the  isolated  part  has  followed  and 
the  unchanged  part  of  the  organ  has  been  subsequently 
extirpated.  Slight  temporary  glycosuria  has  followed 
this  operation,  but  has  quickly  disappeared.  Eemoval  of 
the  atrophied  part  has  been  followed  by  intense  gly- 
cosuria persisting  until  the  thyroid  gland  has  been  re- 
moved for  extraneous  reasons  five  days  later;  death  has 
followed  the  operation.  The  atrophied  pancreatic  tis- 
sue has  consisted  of  strands  and  masses  of  cells  which 
MacCallum  thinks  are  probably  identical  with  those  of 
the  islands  of  Langerhans. 

Objections  to  the  Vieiv  that  Lesions  of  the  Islands 
of  Langerhans  Cause  Diabetes  Mellitus. — Several  writers 
have  claimed  that  changes  in  the  pancreas  usually  asso- 
ciated with  diabetes  mellitus  are  secondary  to  this  dis- 
ease. There  is,  however,  little  probability  that  the 
numerous  lesions  which  have  been  found  are  the  result 
of  one  cause.  All  such  lesions  destroy  the  islands  of 
Langerhans,  but  the  nature  of  the  destructive  change  is 
subject  to  wide  variation. 

Hansemann,*^  Herxheimer*^  and  Karakascheff  ^^ 
have  found  lesions  of  the  islands  of  Langerhans  with 

•■"  MacCallum :  Bull,  of  the  Johns  Hopkins  Hosp.,  1909,  xx,  265. 
**"  Hansemann :    Verhandl.  d,  deutschen  path.  Gesell.,  1902,  iv,  187. 
"Herxhoimer:  Festschr.  f.  Orth.,  Berlin,  1903,  p.  33. 
"hoc.  cit. 


PATHOLOGY  WITH  DIABETES  MELLITUS        347 

diabetes,  but  since  they  have  failed  to  find  such  changes 
in  all  instances  of  the  disease,  maintain  the  belief  that 
diabetes  mellitus  is  referable  to  impairment  of  the  entire 
pancreatic  parenchyma.  Nevertheless,  diabetes  mellitus 
does  not  occur  when  duct-obstruction  has  destroyed  al- 
most the  entire  secreting  parenchyma,  but  has  spared  the 
islands  of  Langerhans,  whereas  diabetes  occurs  when  the 
islands  of  Langerhans  are  destroyed  by  hyaline  degenera- 
tion although  the  secreting  parenchyma  is  intact. 

Both  Herxheimer  and  Karakaseheff  have  modified  the  view 
which  they  first  expressed.  Herxheimer  described  fourteen  cases  of 
diabetes  with  interaeinar  pancreatitis,  but  in  six  instances  found  no 
changes  in  the  islands  of  Langerhans.  In  a  second  article  he  cites 
five  cases  of  interaeinar  pancreatitis  with  sclerosis  and  hyaline  degen- 
eration of  the  islands  of  Langerhans.  Both  acini  and  islands  of  Lan- 
gerhans, he  thinks,  exert  control  upon  carbohydrate  metabolism,  but 
interaeinar  islands  which  have  no  part  in  the  production  of  external 
secretion  have  a  predominant  influence. 

Histological  findings  suggesting  transition  from  acini  to  islands  of 
Langerhans  have  led  Herxheimer  to  believe  that  islands  of  Langerhans 
may  be  formed  from  the  secreting  acini;  such  newly-formed  acini,  he 
thinks,  may  replace  those  which  have  been  destroyed.  The  same 
appearances,  on  the  contrary,  have  suggested  to  Karakascheff  that 
islands  of  Langerhans  form  secreting  acini,  replacing  acini  which  have 
undergone  degeneration.  Although  the  acini,  he  thinks,  control  carbo- 
hydrate metabolism,  destruction  of  islands  of  Langerhans  hastens  onset 
of  diabetes,  for  islands  of  Langerhans  are  constantly  replacing  acini 
which  degenerate  and  disappear.     The  view  is  wholly  speculative. 

A  few  observers  have  claimed  that  severe  lesions  of 
the  islands  of  Langerhans  may  be  unaccompanied  by 
diabetes.  Ohlmacher  has  found  advanced  hyaline  de- 
generation with  no  glycosuria,  but  thinks  that  vicarious 
hypertrophy  of  those  islands  which  have  not  been  de- 


348  DISEASE  OF  THE  PANCREAS 

stroyed  explains  the  absence  of  diabetes.  Trivial  lesions 
without  diabetes  have  been  described  by  Sauerbeck. 
Hansemann,  who  does  not  believe  that  islands  of  Lan- 
gerhans  control  carbohydrate  metabolism,  admits  that  he 
has  never  found  in  the  absence  of  diabetes  mellitus  lesions 
of  the  islands  of  Langerhans  similar  to  those  which  occur 
in  association  with  the  disease. 

Reitmann  prefaces  his  description  of  amyloid  de- 
generation of  the  islands  of  Langerhans  with  the  state- 
ment that  he  has  searched  the  literature  of  the  subject 
in  vain  for  an  instance  in  which  advanced  lesions  of  the 
islands  of  Langerhans  have  been  unaccompanied  by  gly- 
cosuria. In  two  cases  death  occurred  as  the  result  of  un- 
complicated pulmonary  tuberculosis ;  the  greater  number 
of  the  islands  of  Langerhans  were  the  seat  of  amyloid 
degeneration ;  amyloid  substance  was  deposited  about  the 
capillaries  and  the  cells  were  destroyed  or  much  reduced 
in  size.     The  secreting  parenchyma  was  entirely  normal. 

The  well-known  observation  that  glycosuria  of  dia- 
betes may  disappear  as  the  result  of  various  intercurrent 
infections,  and  of  cachexia,  may  explain  its  absence  in 
association  with  amyloid  degeneration  of  the  islands  of 
Langerhans.  Minkowski  found  that  glycosuria  produced 
by  extirpation  of  the  pancreas  of  dogs  may  disappear 
before  death  when  emaciation  is  advanced,  and  may  cease 
with  the  onset  of  complications  such  as  suppurative  peri- 
tonitis. Naunyn  ^^  has  given  special  attention  to  the  com- 
plications of  diabetes  which  inhibit  glycosuria;  one  of 
the  most  frequent  of  these  complications  is  tuberculosis. 


"Naunyn:  Der    Diabetes    mellitus.    Nothnagel's    Spec.    Path.    u. 
Ther.,  Vienna,  1898,  vii,  part  vi. 


PATHOLOGY  WITH  DIABETES  MELLITUS        349 

Disappearance  of  glycosuria  occurs  when  the  patient 
becomes  cachectic,  and  has  been  observed  even  when 
cachexia  has  been  the  result  of  uncomplicated  diabetes. 
In  two  cases  cited  by  Naunyn  diabetes  had  existed  at  least 
five  years,  yet  the  onset  of  cachexia,  accompanying  tuber- 
culosis in  one  instance  and  nephritis  in  the  other,  was 
followed  by  disappearance  of  glycosuria,  which  failed 
to  reappear  even  when  glucose  was  administered  with  the 
food. 

In  some  instances  in  which  pancreatic  lesions  have 
been  found  at  autopsy,  urinary  examination  has  been 
limited  to  the  period  preceding  death.  In  such  cases 
diabetes  may  have  existed  before  onset  of  cachexia,  al- 
though urinary  tests  fail  to  record  its  presence.  With 
amyloid  degeneration  islands  of  Langerhans  are  injured 
by  a  lesion  which  is  always  associated  with  advanced 
cachexia. 

Relationship  of  Diabetes  Mellitus  to  Organs  other 
than  the  Pancreas. — Most  writers  agree  that  cases  occur 
in  which  no  abnormality  of  the  pancreas  is  demonstrable. 
Case  V  (page  339),  in  which  the  normal  pancreas  of 
a  child  ten  years  old  weighed  45  Gm.,  may  serve  as  an 
example.  Careful  investigation  of  the  histology  of  the 
pancreas  has  materially  diminished  the  frequency  with 
which  normal  pancreas  has  been  found  in  association 
with  diabetes  mellitus.  The  statistics  of  Windle  record 
the  occurrence  of  a  normal  pancreas  in  47  per  cent,  of 
one  hundred  and  thirty-nine  cases  of  diabetes,  whereas 
among  cases  collected  on  page  321  only  11.8  per  cent, 
are  without  lesion  or  abnormality  of  the  gland,  trivial 
lesions  which  are  usually  unaccompanied  by  diabetes  be- 
ing excluded.    Among  ninety  cases  of  diabetes  examined 


350  DISEASE  OF  THE  PANCREAS 

by  Cecil  an  even  smaller  proportion — namely,  6.6  per 
cent. — exhibited  no  abnormality  of  the  pancreas.  The 
existence  of  such  cases  does  not  weaken  the  evidence 
in  favor  of  the  pancreatic  origin  of  the  disease  in  other 
instances,  for  abundant  experimentation  has  demon- 
strated the  complexity  of  carbohydrate  metabolism  and 
has  shown  that  the  central  nervous  system  and  the  liver 
exert  an  important  influence  in  regulating  the  amount  of 
sugar  in  the  blood,  while  removal  of  an  excess  present  in 
the  blood  is  effected  by  the  kidneys. 

The  experimental  observations  upon  temporary  glyco- 
suria caused  by  changes  in  the  central  nervous  system, 
the  liver,  and  the  kidneys,  have  been  followed  by  the 
study  of  cases  in  which  glycosuria,  or  not  infrequently 
permanent  diabetes,  has  been  associated  with  lesions  of 
these  organs  in  human  cases;  but  while  the  relationship 
of  the  pancreas  to  diabetes  has  been  very  thoroughly 
established  both  by  experimentation  and  ol)servation,  the 
relationship  of  lesions  affecting  other  organs  is  much 
more  obscure.  Moreover,  diabetes  has  been  found  to 
accompany  certain  relatively  uncommon  diseases — for  ex- 
ample, exophthalmic  goitre  and  acromegaly — with  such 
frequency  that  the  association  can  not  be  regarded  as 
accidental.  In  some  instances  in  which  diabetes  has  been 
supposed  to  be  the  obscure  result  of  a  condition  recog- 
nizable during  life,  it  is  in  reality  secondary  to  a  leeion 
of  the  pancreas  the  existence  of  which  is  not  recognizable 
unless  an  autopsy  is  performed. 

Arterial  sclerosis,  it  is  well  known,  is  present  in  a 
large  proportion  of  diabetics,  and  diabetic  gangrene  is 
referable,  in  many  cases  at  least,  to  implication  of  the 


PATHOLOGY  WITH  DIABETES  MELLITUS        351 

arteries  supplying  the  extremities.  Grube  ^^  found  arte- 
rial sclerosis  in  sixty-six  of  one  hundred  and  seventy- 
seven  cases  of  diabetes.  G.  Hoppe-Seyler  ^^  and  also 
Fleiner^^  have  described  cases  of  diabetes  in  which 
chronic  interstitial  inflammation  of  the  pancreas  accom- 
panied general  arterial  sclerosis.  Case  XX  of  my  series 
illustrates  this  condition;  here  both  chronic  interacinar 
pancreatitis  and  gangrene  of  the  leg  appear  to  be  the 
result  of  advanced  arterial  sclerosis. 

Hoppe-Seyler**^  studied  a  series  of  cases  in  which 
interacinar  pancreatitis,  occurring  in  association  with 
advanced  arterial  sclerosis,  caused  diabetes  mellitus 
(seven  cases)  or  alimentary  glycosuria  (two  cases).  In 
nine  cases  chronic  inflammation  of  the  pancreas  was 
Ttnaccompanied  by  glycosuria,  and  changes  in  the  islands 
of  Langerhans  were  absent  or  trivial,  whereas  among 
those  cases  in  which  glycosuria  was  present  there  was  a 
close  parallel  between  the  severity  of  diabetes  and  the 
intensity  of  the  changes  in  the  islands  of  Langerhans. 
Hoppe-Seyler  further  studied  the  ability  of  individuals 
with  arterial  sclerosis  to  assimilate  glucose  and  found 
alimentary  glycosuria  in  twenty-six  (42  per  cent.)  of 
sixty-two  cases,  the  condition  being  most  frequent  when 
arterial  sclerosis  was  associated  with  acute  alcoholism. 

Increased  attention  has  recently  been  given  to  the  condition  of 
the  arteries  in  association  with  diabetes,  for  whereas  among  one  hundred 
and  seventy-six  cases  collected  by  Sauerbeck  arterial  sclerosis  has  been 
recorded  twelve  times,  among  one  hundred  and  twelve  cases  since 
recorded  general  ai-terial  sclerosis  together  with  sclerosis  of  the  pan- 

^  Gi-ube :   Zeit.  f .  klin.  Med.,  1895,  xxvii,  465. 

*^Loc.  eit.,  Chap.  IX. 

"  Hoppe-Seyler,  G. :  Deutsches  Arch,  f .  klin.  Med.,  1904,  Ixxxi,  119. 


352  DISEASE  OF  THE  PANCREAS 

creatic  arteries  has  been  noted  in  thirty-two  instances;  sclerosis  of  the 
arteries  of  the  pancreas  alone  in  six. 

Cecil  has  found  sclerosis  of  the  pancreatic  arteries  in  80  per  cent. 
of  ninety  cases  of  diabetes;  the  walls  of  the  small  arteries  are  thick- 
ened, and  in  many  instances  have  undergone  hyaline  degeneration.  The 
incidence  of  arterial  sclerosis  has  increased  rapidly  with  age,  occurring 
in  40  per  cent,  of  diabetics  between  twenty  and  thirty  years  of  age,  in 
75  per  cent,  between  thirty  and  forty,  and  in  all  but  two  instances 
after  the  fortieth  year.  It  is  noteworthy  that  arterial  sclerosis  has 
been  present  in  all  save  five  of  forty-nine  instances  in  which  the  islands 
of  Langerhans  have  exhibited  sclerosis,  and  in  all  save  two  of  twenty- 
seven  instances  in  which  these  islands  have  been  hyaline.  "When 
arterial  sclerosis  causes  chronic  interacinar  pancreatitis,  the  islands 
of  Langerhans  are  implicated  and  diabetes  mellitus  results. 

There  is  abundant  evidence  that  diabetes  accompany- 
ing cirrhosis  of  the  liver  is,  in  the  majority  of  cases  at 
least,  the  result  of  chronic  interstitial  pancreatitis; 
chronic  inflammation  of  the  liver  and  pancreas  coexist 
as  the  result  of  the  same  primary  etiological  factor — for 
example,  alcohol.  Diabetes  with  cirrhosis  is  a  well  recog- 
nized condition,  and  numerous  cases  are  recorded ;  among 
one  hundred  and  twenty-eight  cases  of  diabetes  observed 
in  hospital  clinics  by  NaunjTi,  seven  were  accompanied 
by  cirrhosis,  but  in  his  private  practice,  among  one  hun- 
dred and  fifty-eight  cases,  twenty-two  were  with  cirrhosis. 
I  have  studied  three  cases  in  which  the  two  conditions 
were  associated,  and  in  all  the  pancreas  was  the  seat  of 
chronic  interacinar  inflammation  invading  the  islands  of 
Langerhans.  In  cases  of  diabetes  accompanying  cir- 
rhosis, described  with  autopsy  report  by  Diecklioff  and 
by  Pusinelli,^^  the  pancreas  showed  chronic  inflammatory 

"Pusinelli:  Berliner  klin.  Woch.,  1896,  xxxiii,  739. 


PATHOLOGY  WITH  DIABETES  MELLITUS        353 

changes.  Seven  cases  with  cirrhosis  of  the  liver  and 
interacinar  pancreatitis  occurred  among  ninety  cases  of 
diabetes  studied  by  Cecil. 

The  relationship  of  cirrhosis  of  the  liver  to  chronic 
interstitial  pancreatitis  has  already  been  discussed.  The 
condition  known  as  haemochromatosis  offers  an  excellent 
illustration  of  the  dependence  of  cirrhosis  of  the  liver 
and  chronic  pancreatitis  upon  the  same  etiological  fac- 
tors ;  in  this  condition  diabetes  occurs  as  a  terminal  event, 
when  the  pancreatic  inflammation  which  is  of  the  inter- 
acinar type  has  reached  a  moderate  grade  of  severity. 
It  is  probable  that  the  alimentary  glycosuria  inconstantly 
observed  with  cirrhosis  of  the  liver  by  Colrat,*^  Cou- 
turier,^^ Kraus  and  Ludwig,^*'  and  others,  may  be  the 
result  of  slight  coexisting  alterations  of  the  pancreas. 

The  influence  of  the  nervous  system  upon  the  excretion 
of  sugar  is  shown  by  Claude  Bernard's  puncture  of  the 
floor  of  the  fourth  ventricle  and  by  other  experimental 
injuries  to  the  central  nervous  system.  The  statistics 
of  Higgins  and  Ogden  ^^  show  that  glycosuria  frequently 
follows  injuries  to  the  brain;  they  found  glycosuria  in 
9.3  per  cent,  of  two  hundred  and  twelve  cases  of  trauma- 
tism affecting  the  head,  while  of  forty-five  cases  in  which 
the  skull  was  fractured  glycosuria  followed  in  21.9  per 
cent.  Instances  of  permanent  diabetes  following  cere- 
bral lesions  are  recorded,  but  the  relationship  of  the  dis- 
ease to  the  injury  is  doubtful.     Diabetes  is  occasionally 

*^  Colrat :    Lyons  med.,  1875,  xviii,  553. 
"  Couturier :    Thesis,  Paris,  1875. 

"*  Kraus  and  Ludwig:    Wiener  klin.  Woch.,  1891,  iv,  855,  897. 
■"Higgins  and  Ogden:  Boston  Med.  and  Surg.  Jour,,  1895,  exxxii, 
197. 


354  DISEASE  OF  THE  PANCREAS 

associated  with  tabes  dorsalis  or  with  multiple  sclerosis 
and  has  been  regarded  as  secondary  to  the  nervous 
lesions. 

Of  greater  interest,  in  view  of  the  experiments  of 
Claude  Bernard,  is  the  recorded  association  of  lesions 
of  the  medulla  with  diabetes.  In  cases  of  multiple  scle- 
rosis described  by  Weichselbaum  ^^  and  by  Eichardiere  ^^ 
plaques  occupied  the  floor  of  the  fourth  ventricle.  Re- 
markable instances  in  which  small  tumors  have  en- 
croached upon  the  floor  of  the  fourth  ventricle  are  re- 
corded by  Levrat-Perroton,^^  Von  Eecklinghausen,^^  and 
Verron.^*'  In  a  case  recorded  by  Michael  a  cysticercus 
occupied  the  fourth  ventricle.  It  is  not  impossible  that 
such  conditions  may  act  as  exciting  causes  in  the  pro- 
duction of  diabetes. 

Glycosuria  following  the  administration  of  phlorhizin 
has  already  been  mentioned.  Since  most  observers  are 
agreed  that  with  this  form  of  glycosuria  the  amount  of 
sugar  in  the  blood  is  not  increased,  the  possibility  has 
suggested  itself  that  the  kidneys  are  so  altered  that  they 
admit  the  passage  of  the  sugar  normally  present  in  the 
blood.  The  occurrence  of  an  analogous  renal  diabetes 
in  human  beings  has  been  suspected.  Klemperer  ^'^  has 
described  a  case  of  diabetes  associated  with  nephritis. 
The  amount  of  sugar  in  the  blood  was  not  greater  than 
normal,  and  after  the  administration  of  150  Gm.  of  gli;- 

■"  Weichselbaum :    Wiener  med.  Woeh.,  1881,  xxxi,  913. 

■^  Richardiere :  Rev.  de  med.,  1886. 

"  Levrat-Pen-oton :  Thesis,  Paris,  1859. 

"  Von  Recklinghausen :    Virchow's  Arch.,  1864,  xxx,  360. 

"  Verron  :  Thesis,  Paris,  1878. 

"Klemperer:    Berliner  klin,  Woch.,  1896,  xxxiii,  571. 


PATHOLOGY  WITH  DIABETES  MELLITUS        355 

cose  the  amount  of  sugar  in  the  urine  and  in  the  blood 
was  not  increased.  Cases  in  which  pre-existing  nephritis 
has  been  associated  with  diabetes  are  cited  by  Naunyn, 
and  by  Eger,^«  but  since  they  may  be  referable  to  the 
more  or  less  accidental  coexistence  of  the  two  conditions, 
they  do  not  furnish  strong  evidence  that  glycosuria  is 
dependent  upon  the  renal  lesion, 

Richter™  has  studied  experimentally  the  relationship  of  glycosuria 
to  lesions  of  the  kidney.  Small  doses  of  eon'osive  sublimate  injected 
into  the  venous  circulation  of  rabbits  cause  not  only  albuminuria,  but 
glycosuria  as  well.  Very  small  doses  may  cause  glycosuria,  but  no 
albuminuria;  and  since  the  amount  of  sugar  in  the  blood  is  found  to 
be  increased,  Richter  does  not  think  that  the  glycosuria  should  be 
attributed  to  alterations  of  the  kidneys.  Glycosuria  produced  by 
phlorhizin  is,  moreover,  diminished  or  prevented  if  a  lesion  of  the 
kidney  is  produced  by  the  administration  of  aloin  or  potassium  chro- 
mate.  Elbinger  and  Selig*'"  rendered  dogs  diabetic  and  then  adminis- 
tered cantharidin  in  order  to  injure  the  kidneys.  They  found  that 
glycosuria  diminished  with  the  onset  of  renal  changes.  Lesions  of 
the  kidney  in  animals  appear  to  retard  rather  than  favor  the  excretion 
of  sugar,  and  it  has  been  observed  that  glycosuria  in  cases  of  diabetes 
not  infrequently  diminishes  with  the  appearance  of  albuminuria. 
True  renal  diabetes  may  occur,  perhaps  as  the  result  of  some  peculiar 
injury  to  the  kidney,  but  its  existence  has  not  been  demonstrated. 

The  association  of  diabetes  with  diseases  of  certain 
ductless  glands  has  considerable  interest.  Exophthalmic 
goitre  with  diabetes  not  infrequently  occurs ;  and  Hanne- 
mann,^^  who  has  made  a  careful  survey  of  the  literature, 

""Eger:  Deutsche  med.  Woeh.,  1899,  xxv,  844. 
'"Richter:  Zeit.  f.  klin.  Med.,  1900,  xli,  160. 

°°  Elbinger  and  Selig:  Verhandl.  d,  19  Cong.  f.  innere  Med.,  1901, 
416. 

"Hannemann:  Inaug.  Diss.,  Berlin,  1895. 


356  DISEASE  OF  THE  PANCREAS 

has  been  able  to  collect  fifteen  cases  in  wbich  the  two 
diseases  have  been  associated;  at  least  a  dozen  writers 
have  observed  temporary  glycosuria  with  exophthalmic 
goitre.  Alimentary  glycosuria  with  exophthalmic  goitre 
was  first  observed  by  Kraus  and  Ludwig;  later  Chvos- 
tek  ^^  reached  the  conclusion  that  it  occurs  in  69  per  cent, 
of  all  cases,  but  Strauss  ^^  observed  glycosuria  after  the 
administration  of  100  Gm.  of  grape  sugar  in  only  three 
of  nineteen  cases.  Glycosuria  following  the  therapeutic 
use  of  thyroid  extract  has  been  observed. 

Eppinger,  Falta  and  Rudinger^*  have  claimed  that  the 
thyroid  gland  inhibits  the  action  of  the  pancreas;  gly- 
cosuria, which  may  occur  with  exophthalmic  goitre  is 
referable,  they  suggest,  to  abnormal  activity  of  the  thy- 
roid gland.  The  occurrence  of  pancreatic  lesion  in  asso- 
ciation with  combined  exophthalmic  goitre  and  diabetes 
renders  this  hypothesis  unnecessary. 

The  following  case  of  exophthalmic  goitre  has  been 
described  by  Dr.  Morris  Manges  ^^and  is  included  in  the 
series  of  cases  studied  by  Cecil. 

A  woman  aged  forty  years  has  suffered  with  diabetes  during  six 
months.  The  urine  contains  as  much  as  5  per  cent,  of  sugar.  There 
is  exophthalmos  and  tachycardia.  The  thyroid  is  enlarged  and  finn 
and  exhibits  glandular  hyperplasia.  The  pancreas  is  small  and  weighs 
45  Gm. ;  there  is  chronic  interacinar  pancreatitis.  The  acini  axe  small 
and  in  places  separated,  in  places  wholly  replaced  by  fibrous  tissue, 
infiltrated  with  lymphoid  and  plasma  cells.     Islands  of  Langerhans  are 


"  Chvostek:  Wiener  klin.  AVoch.,  1892,  v,  251,  267,  325. 
°*  Strauss :  Deutsche  med.  Woch.,  1897,  xxiii,  275. 
"Loc.  dt.,  Chap.  V. 
"  Manges,  M. :  Mt.  Sinai  Hosp.  Rep.,  1901,  ii,  59. 


PATHOLOGY  WITH  DIABETES  MELLITUS        357 

fairly  numerous,  but  small;  where  sclerosis  is  advanced  they  are  sur- 
rounded and  invaded  by  fibrous  stroma,  many  being  almost  wholly 
destroyed. 

The  close  relation  between  exophthalmic  goitre  and 
myxcedema  gives  special  significance  to  the  following  case 
(recorded  by  Cecil),  in  which  associated  myxoedema  and 
diabetes  mellitus  accompanied  chronic  inflammation  of 
the  thyroid  gland  and  pancreas. 

A  woman,  seventy-four  years  of  age,  was  admitted  to  the  Pres- 
byterian Hospital  with  gradual  loss  of  mental  power  and  thickening 
of  the  subcutaneous  tissue;  the  skin  was  dry  and  scaly;  the  hair 
and  nails  were  brittle,  and  the  tongue  was  thickened.  There  was  no 
sugar  in  the  urine.  Rapid  improvement  followed  treatment  with  thy- 
roid extract.  A  year  and  a  half  later  the  patient  was  again  admitted 
with  thirst,  polyuria  and  glycosuria,  the  urine  containing  4  per  cent, 
of  sugar.  Myxoedema  was  much  improved.  Two  years  later  death 
occurred  with  coma.  The  thyroid  gland  weighs  8.5  Grm.;  alveoli  are 
almost  completely  destroyed  by  fibrous  tissue.  The  pancreas  is  tough 
and  weighs  120  Gm.  There  is  advanced  interaeinar  pancreatitis  and 
lipomatosis.     The  islands  of  Langerhans  show  considerable  sclerosis. 

It  is  not  improbable  that  chronic  inflammatory  changes 
in  thyroid  and  pancreas  are  referable  to  the  same  cause. 
Stern  ^^  cites  two  cases  in  which  diabetes  has  preceded 
exophthalmic  goitre,  five  cases  in  which  the  two  diseases 
have  appeared  simultaneously,  and  fourteen  cases  in 
which  diabetes  has  occurred  in  individuals  who  have  been 
suffering  with  exophthalmic  goitre. 

Added  interest  is  attached  to  the  remarkable  associa- 
tion of  acromegaly  with  diabetes  by  the  fact  that  the 
former  disease  is  not  infrequently  accompanied  by  indu- 

°*  Stem :  Jour,  of  the  American  Med.  Assn.,  1902,  xxxix,  972. 


358  DISEASE  OF  THE  PANCREAS 

ration  of  the  interstitial  tissue  of  the  pancreas.  Hanse- 
mann  *'^  found  diabetes  present  in  twelve  of  ninety-seven 
reported  cases  of  acromegaly,  a  case  of  his  own  included. 
Among  one  hundred  and  seventy-six  cases  of  acromegaly 
collected  by  Borchardt  ^^  diabetes  occurred  in  sixty-three 
(35.5  per  cent.) ;  in  eight  cases  there  was  alimentary 
glycosuria. 

A  review  of  cases  described  with  autopsy  reports 
shows  that  chronic  pancreatitis  has  been  repeatedly  ob- 
served in  association  with  acromegaly.  Dallemange  ®^ 
found  chronic  interstitial  inflammation  of  the  gland  in 
two  cases  of  acromegaly,  one  of  which  was  associated 
with  diabetes.  In  a  case  of  acromegaly  with  diabetes 
described  by  Hansemann  chronic  pancreatitis  was  pres- 
ent. In  a  case  with  glycosuria,  recorded  by  Frankel, 
Stadelmann,  and  Benda,^''  the  pancreas  showed  a  condi- 
tion described  as  nodular  hypertrophy,  while  in  a  second 
with  diabetes  no  lesion  was  noted,  but  here  no  microscopic 
examination  was  made.  In  one  case  of  acromegaly  with- 
out diabetes,  described  by  the  writers  just  named,  and  in 
a  similar  case  described  by  Mitchell  and  Le  Count,'^^ 
chronic  inflammation  of  the  pancreas  was  demonstrable. 
Pineles  '^^  found  at  autopsy  upon  a  case  of  acromegaly 
with  persistent  diabetes  purulent  pancreatitis  with  fat 

*'  Hansemann :  Berliner  klin.  Woch.,  1897,  xxxiv,  417. 

**  Borchardt :  Zeit.  f .  klin.  Med.,  1908,  Ixvi,  332. 

**  Dallemange :  Arch,  de  med.  exper.  et  d'anat.  path.,  1895,  vii,  589. 

'"  Frankel,  Stadelmann  and  Benda :  Deutsche  med.  Woch.,  1901, 
xxvii,  513,  564, 

"  Mitchell  and  Le  Count :  New  York  Med.  Jour.,  1899,  Ixix,  517, 
566,  595. 

"Pineles:  Jahrb.  d.  Wiener  k.  k.  Krankenanst.,  Jahrg.,  1895, 
Vienna,  1897. 


PATHOLOGY  WITH  DIABETES  MELLITUS        359 

necrosis,  but  the  presence  of  pre-existing  chronic  inflam- 
mation can  only  be  suspected. 

The  following  case  of  acromegaly  has  been  described 
by  Dr.  Charles  Norris :  ^^ 

A  man,  thirtyi-three  years  old,  had  suffered  with  headache  and 
vertigo;  there  was  loss  of  vision,  with  atrophy  of  the  optic  nerves; 
the  jaw,  nose,  hands  and  feet  had  undergone  progressive  enlargement. 
Glycosuria  had  been  present  during  twenty-two  months. 

The  site  of  the  pituitary  gland  is  occupied  by  a  large  adenomatous 
tumor.  The  pancreas  weighs  170  Gm.  There  is  no  increase  of  the 
interstitial  tissue  of  the  pancreas  ^*  and  the  glandular  acini  are  normal. 
Islands  of  Langerhans  are  numerous,  and  many  are  normal.  Some  of 
these  bodies  are  enlarged,  one  measuring  600  micromillimetres  in 
diameter,  and  their  cells  were  columnar;  they  exhibit  the  adenoma-like 
hypertrophy  previously  described.  The  capillaries  of  such  interacinar 
islands  were  thickened  by  newly-formed  fibrous  tissue.  In  a  few  islands 
of  Langerhans  there  is  advanced  hyaline  degeneration. 

The  cases  cited  indicate  that  diabetes  mellitus  accom- 
panying acromegaly  is  referable  to  a  pancreatic  lesion. 

Production  of  glycosuria  by  injection  of  extracts  of 
adrenal  gland  into  animals  has  suggested  the  possible 
association  of  diabetes  mellitus  and  disease  of  the  adrenal 
glands.  Lepine  "^^  has  described  a  case  in  which  with 
diabetes  there  has  been  tumor  of  the  adrenal ;  this  tumor 
is  described  as  sarcoma,  but  has  perhaps  been  an  hyper- 
nephroma.'^*^    Lepine  has  collected  from  the  literature 

"  Norris :    Trans,  of  the  New  York  Path.  Soc,  1907,  vii,  19. 

"  With  the  permission  of  Dr.  Norris  this  case  has  been  included  in 
the  series  of  Dr.  Cecil. 

"Lepine:    Rev.  de  med.,  1906,  xxvi,  537. 

"  See  Meakins :  A  Malignant  Adenoma  of  the  Adrenal  with  Trans- 
formation into  Sarcomatous  Tissue.  Med.  and  Surg.  Rep.  of  the  Pres- 
byterian Hosp.  of  New  York,  1908,  viii,  271. 


360  DISEASE  OF  THE  PANCREAS 

of  the  subject  three  instances  of  diabetes  occurring  in 
individuals  with  lesions  of  the  adrenal,  in  one  instance  a 
tumor.  He  believes  that  the  evidence  which  is  available 
is  insufficient  to  establish  the  occurrence  of  diabetes  mel- 
litus  referable  to  a  lesion  of  the  adrenal  glands. 

Diagnosis  of  Pancreatic  Diabetes. — The  occurrence  of 
glycosuria  and  diabetes  in  association  with  lesions  of 
the  nervous  system,  and  after  the  administration  of  many 
toxic  substances,  indicates  the  complexity  of  carbohy- 
drate metabolism.  Normal  assimilation  of  sugar  doubt- 
less depends  upon  a  variety  of  factors,  among  which 
integrity  of  the  pancreas,  though  very  important,  does 
not  stand  alone,  and  disturbances  of  carbohydrate 
metabolism  may  be  the  result  of  conditions  affecting 
other  organs.  Hence  the  occurrence  of  diabetes  unac- 
companied by  alterations  of  the  pancreas  does  not  furnish 
evidence  to  disprove  the  relationship  of  the  disease  to 
lesions  of  the  gland.  Nevertheless  the  occurrence  of  pan- 
creatic diabetes  is  much  more  frequent  than  has  been 
supposed.  Moreover,  the  foregoing  discussion  has  shown 
that  in  many  instances,  at  least,  diabetes,  associated  with 
such  conditions  as  arterial  sclerosis,  cirrhosis  of  the 
liver,  haBmochromatosis,  exophthalmic  goitre  and  acro- 
megaly, is  secondary  to  a  lesion  of  the  pancreas  accom- 
panying these  diseases.  Arterial  sclerosis  produces 
chronic  interstitial  inflammation  of  the  pancreas,  whereas 
cirrhosis  of  the  liver  accompanies  chronic  pancreatitis, 
because  both  are  the  result  of  the  same  etiological  factor. 
The  relationship  of  the  nervous  system  of  the  kidneys, 
and  of  the  adrenal  glands  to  diabetes  is  more  obscure. 

The  attempt  has  been  unsuccessfully  made  to  define 
certain  clinical  symptoms  characteristic  of  diabetes  when 


PATHOLOGY  WITH  DIABETES  MELLITUS        36l 

due  to  lesions  of  the  pancreas.  Lancereaux,  notably,  has 
described  a  special  type  of  diabetes  referable  to  pan- 
creatic disease  and  characterized  by  extreme  emaciation, 
in  company  with  intense  thirst,  voracious  appetite,  and 
abundant  polyuria.  He  designates  the  condition  ''dia- 
bete  maigre,"  and  distinguishes  it  from  diabetes  with 
obesity,  ''diabete  gras,"  unaccompanied  by  pancreatic 
disease.  His  views  have  received  some  acceptance,  but 
few  clinicians  maintain  that  it  is  possible  to  recognize 
the  sharp  distinction  claimed  by  him.  Many  writers,  Le- 
pine,  Hansemann,  Williamson,  among  others,  have  on 
the  one  hand  cited  cases  in  which  emaciation  was  absent, 
though  diabetes  accompanied  pancreatic  disease;  while 
on  the  other  hand,  in  emaciated  patients  suffering  with 
diabetes,  they  have  discovered  no  alteration  of  the  pan- 
creas. Eemoval  of  the  gland  in  animals  is  followed  by 
diabetes  with  rapid  emaciation,  absence  of  pancreatic 
secretion  being  followed  by  grave  disturbances  of  diges- 
tion and  absorption.  In  human  cases,  however,  diabetes 
may  be  caused  by  lesions  of  the  gland  which  destroy  the 
islands  of  Langerhans,  yet  leave  almost  intact  the  secret 
ing  parenchyma. 

Study  of  the  pathology  of  the  pancreas  has  made  it 
possible  to  define  with  accuracy  the  conditions  under 
which  glycosuria  occurs  as  a  symptom  of  pancreatic  dis- 
ease. The  presence  of  diabetes  mellitus  is  not  conclusive 
evidence  that  there  is  a  lesion  of  the  interacinar  islands ; 
nevertheless,  in  only  13  per  cent,  of  cases  is  diabetes  un- 
accompanied by  disease  of  these  bodies.  It  is  noteworthy 
that  diabetes  with  normal  pancreas  occurs  almost  exclu- 
sively during  the  early  period  of  life.  Among  two  hun- 
dred and  eighty-eight  cases  of  diabetes  previously  cited 


362  DISEASE  OF  THE  PANCREAS 

age  of  the  patient  has  been  recorded  in  one  hundred  and 
forty-four,  and  among  ninety  eases  of  Cecil  age  has  been 
recorded  in  eighty-eight.  The  incidence  of  normal  and 
diseased  pancreas  in  these  two  hundred  and  thirty-two 
cases  of  diabetes  has  been  as  follows : 


Age  in  years 

{? 

10 
to 
19 

20 
to 
29 

30 
to 
39 

40 
to 
49 

60 
to 
59 

60 
to 
69 

70 
to 
79 

80 
to 
89 

With  normal  pancreas 

2 

10 

10 

6 

2 

1 

0 

1 

1 

With  lesion  of  the  pancreas . . 

.   1 

7 

24 

30 

30 

4S 

37 

21 

1 

Total 

.  3 

17 

34 

36 

32 

49 

37 

22 

2 

During  the  second  decade  of  life,  when  diabetes  mel- 
litus  is  relatively  uncommon,  a  majority  of  cases  exhibit 
no  pancreatic  lesion;  such  cases  are  fairly  numerous  in 
the  third  decade,  but  at  a  later  period  are  infrequent. 
Diabetes  occurring  during  middle  life  and  later  is  with 
few  exceptions  referable  to  a  pancreatic  lesion.  Lithiasis 
and  carcinoma,  like  the  same  changes  in  other  organs, 
usually  occur  after  the  fortieth  year,  whereas  various 
types  of  pancreatic  inflammation  have  the  age  incidence 
common  to  cirrhosis  of  the  liver,  chronic  nephritis,  and 
chronic  inflammatory  changes  in  other  organs.  Inter- 
acinar  pancreatitis  has  occurred  in  one  hundred  and 
thirty-one  of  two  hundred  and  thirty-two  cases  classified 
by  age  in  the  table ;  the  lesion  is  uncommon  in  early  life, 
but  after  the  fortieth  year  accompanies  two-thirds  of  all 
cases  of  diabetes.  The  frequency  of  this  change  in  later 
life  is  in  part  dependent  upon  its  association  with  arterial 
sclerosis. 

Study  of  the  histological  changes  which  occur  with 
diabetes  define  the  relationship  of  glycosuria  to  steator- 
rhcea,  azotorrhcea  and  other  evidence  of  insufficiency  of 


PATHOLOGY  WITH  DIABETES  MELLITUS        363 

pancreatic  juice  in  the  intestine.  Since  islands  of  Lan- 
gerhans  may  be  destroyed,  although  the  secreting  acini 
are  almost  wholly  unaffected,  diabetes  may  occur  without 
digestive  symptoms;  most  cases  of  pancreatic  diabetes 
belong  to  tliis  group.  Hemorrhagic  necrosis,  suppura- 
tive pancreatitis,  diffuse  carcinoma,  destroy  both  ele- 
ments of  the  gland  and  diabetes  mellitus  follows  only  in 
the  relatively  infrequent  instances  in  which  almost  the 
entire  organ  is  destroyed. 

Obstruction  to  the  outflow  of  pancreatic  secretion  does 
not  cause  glycosuria,  and  the  interlobular  pancreatitis 
which  follows  occlusion  of  the  pancreatic  ducts  is  accom- 
panied by  diabetes  only  when  the  lesion  has  reached  the 
advanced  stage  in  which  islands  of  Langerhans  are  in- 
jured. With  calculi,  cyst,  or  new  growth  compressing 
the  duct  there  may  be  fatty  stools  but  no  glycosuria; 
among  twenty-nine  instances  of  pancreatic  disease  with 
steatorrhoea  Fitz  ^'^  found  diabetes  in  only  eleven. 

Application  of  chemical  methods  to  examination  of  the 
faeces,  on  the  one  hand,  would  doubtless  demonstrate  with 
greater  frequency  the  existence  of  disturbed  pancreatic 
digestion  in  those  cases  in  which  with  lesions  of  the 
secreting  apparatus  of  the  glands  glycosuria  is  absent. 
Determination  of  the  power  to  assimilate  glucose,  on  the 
other  hand,  would  not  infrequently  reveal  minor  changes 
in  the  gland. 

Wille "  has  observed  alimentary  glycosuria  in  association  with 
lesions  of  the  pancreas,  and  thinks  that  this  symptom  may  be  regarded 
as  an  index  to  the  presence  of  pancreatic  disease.     The  ability  to  assimi- 

""  Loc.  cit.,  p.  90. 

"  Wille :    Deutsches  Arch,  f .  klin.  Med.,  1899,  Ixiii,  546. 


364  DISEASE  OF  THE  PANCREAS 

late  sugar  was  tested  in  eight  hundred  patients  suffering  with  a  great 
variety  of  diseases.  In  the  morning,  before  other  food  had  been  taken, 
was  administered  from  70  to  100  Gm.  of  grape  sugar  dissolved  in  a  half 
litre  of  tea  or  coffee.  The  urine  was  voided  just  before  the  sugar  was 
taken  and  was  then  tested  at  intervals  of  two  hours;  when  the  test 
was  positive,  sugar  usually  appeared  at  the  end  of  two  hours.  Of 
eight  hundred  individuals  upon  whom  this  test  was  made,  seventy-seven 
subsequently  died  and  autopsies  were  performed.  Alimentary  glyco- 
suria had  been  found  in  fifteen  of  those  who  came  to  autopsy,  and 
in  ten  of  these  were  present  grave  lesions  of  the  pancreas,  chronic 
interstitial  inflammation,  or  carcinoma  of  the  gland,  either  primary  or 
secondary  to  tumors  in  the  stomach,  liver,  or  gall-bladder. 

Altliougli  alimentary  glycosuria  may  occur  in  the 
absence  of  pancreatic  disease  and  is  not  infrequently 
associated  with  a  variety  of  conditions,  notably  hysteria 
and  other  neuroses,  its  presence  suggests  (Wille,  Hoppe- 
Seyler'^^)  the  existence  of  pancreatic  lesion  and  has 
considerable  value  for  diagnosis. 

^^  hoc.  eit.,  p.  235. 


CHAPTER  XVI . 

HEMOCHROMATOSIS    AND    BRONZED    DIABETES. 

The  relationship  between  diabetes  and  lesions  of  the 
pancreas  is  well  illustrated  by  the  disease  known  as 
haBmochromatosis,  a  disturbance  of  the  metabolism  of 
iron,  which,  though  infrequent,  has  excited  much  interest 
on  account  of  its  remarkable  character  and  obscure  patho- 
genesis. Its  identity  with  "diabete  bronze" — or  the 
diabetes  with  pigmentation  and  cirrhosis,  of  French 
writers — ^is  now  recognizable. 

Under  the  designation  ''haemochromatosis"  Von 
Recklinghausen  ^  (1889)  has  described  a  condition  of  pig- 
mentation affecting  various  organs.  Brown  pigment, 
which  he  has  thought  is  derived  from  the  haemoglobin  of 
the  blood,  is  deposited  within  certain  tissues  and  gives 
to  them  macroscopic  pigmentation. 

The  anatomical  character  of  this  generalized  pigmen- 
tation is  clearly  defined  by  Von  Recklinghausen.  Most 
of  the  glands  of  the  body  assume  a  deep  brown  color,  and 
within  their  secreting  cells  are  found  reddish-yeUow  or 
ochre-colored  granules.  Microchemical  reactions  prove 
that  this  pigment  contains  iron.  In  the  liver  pigment  is 
present  in  the  parenchymatous  cells  and  in  Kiipffer's 
cells.  A  second  kind  of  pigment,  distinguishable  from 
the  first  by  its  finer  granules  of  pure  yeUow  color,  is 
found  in  the  smooth  muscle  cells  of  the  stomach  and 

^Von  Recklinghausen:  Tagebl.  d.  62  Versamml.  deutseh.  Natur- 
forscher  u.  Aerzte  in  Heidelberg,  1889,  324. 

365 


366  DISEASE  OF  THE  PANCREAS 

intestines,  of  the  blood-  and  lymph-vessels,  rarely  in  the 
muscle  of  the  urinary  bladder,  ureters,  and  vas  deferens. 
It  also  exists  in  the  connective-tissue  cells  of  certain 
localities — for  example,  Glisson's  capsule,  the  splenic 
trabeculae,  and  the  sheaths  of  blood-vessels.  This  sec- 
ond pigment  does  not  give  the  reactions  characteristic  of 
iron.  Von  Recklinghausen  calls  the  iron-containing  pig- 
ment "haemosiderin,"  the  iron-free  pigment  ''haemo- 
fuscin."  The  use  of  these  names  does  not  imply  that 
we  have  means  of  identifying  the  substances  as  definite 
chemical  compounds.  Von  Recklinghausen  thinks  that 
haemofuscin,  as  well  as  the  iron-containing  haemosiderin, 
is  derived  from  haemoglobin.  In  his  cases  of  generalized 
pigmentation  there  was  an  associated  cirrhosis  of  the 
liver. 

Von  Recklinghausen  studied  twelve  cases  which  he 
regarded  as  examples  of  local  and  general  haemochro- 
matosis.  He  defined  haemochromatosis  as  a  condition 
of  pathological  pigmentation  due  to  the  deposition  of 
pigment  derived  from  the  blood. 

There  isj  however,  a  local  condition  which  has  been 
identified  with  haemochromatosis  by  several  observers; 
pigmentation  of  the  intestine  caused  by  deposition  of 
fine  yellow  granules  in  the  smooth  muscle  cells  has  been 
carefully  studied  by  Goebel  ^  and  others.  In  adults  mod- 
erate pigmentation  is  almost  constant,  and  the  amount 
of  pigment  increases  with  age.  With  wasting  diseases — 
for  example,  tuberculosis  and  carcinoma — there  may  be 
an  accumulation  equal  to  that  present  in  advanced  age. 
In  sixteen  of  one  hundred  bodies  studied  by  Goebel  the 

'  Goebel :  Virchow's  Arch.,  1894,  exxxvi,  482. 


HiEMOCHROMATOSIS  367 

pigment  deposit  was  of  sufficient  magnitude  to  cause 
macroscopic  discoloration,  characterized  by  him  as  rust 
brown.  This  accumulation  of  pigment  within  the  smooth 
muscle  cells  of  the  intestine  is  apparently  an  accentuation 
of  a  physiological  process  much  more  closely  related 
to  brown  atrophy  of  the  heart  than  to  haemochromatosis. 
Von  Recklinghausen's  description  defines  a  condition 
presenting  no  close  similarity  to  any  form  of  local  pig- 
mentation with  wliich  we  are  familiar.  The  important 
features  of  this  description  are:  (1)  The  presence  in  the 
epithelial  cells  of  various  glands,  notably  the  liver  and 
pancreas,  of  an  iron-containing  pigment.  (2)  The  pres- 
ence of  an  iron-free  pigment  in  smooth  muscle  cells  of  the 
gastro-intestinal  tract,  and  of  the  blood-  and  lymph- 
vessels,  and  in  certain  cells  of  connective  tissue.  (3) 
The  association  of  cirrhosis  of  the  liver  with  pigmenta- 
tion. To  this  condition,  apparently  a  distinct  pathologi- 
cal entity,  the  term  haemochromatosis  should  be  limited. 

Prior  to  Von  Reeklinglaausen's  publication  several  observers  bad 
studied  instances  of  wide-spread  pigmentation.  Quincke^  in  1877 
observed  witb  anaemia  a  deposition  of  iron  in  various  organs,  notably 
in  the  liver  and  spleen,  and  in  one  instance  found  macroscopic  pigmen- 
tation of  the  liver  and  pancreas.  Tillmanns^  described  brown  pigmen- 
tation of  the  liver,  of  the  abdominal  lymphatic  glands,  and  in  less 
degree  of  the  spleen  and  pancreas,  in  a  man  who  had  sustained  a 
fracture  of  the  pelvis  two  months  before  death  and,  the  observer 
thought,  a  contusion  of  the  liver.  Hindenlang  ^  observed  in  association 
with  morbus  maculosus  Werlhofii  pigmentation  of  the  glands  of  the 

*  Quincke :  Festsch.  dem  Andenken  Albrechts  von  Haller  gewid- 
met.     Bern,  1877,  37. 

*Tillmanns:  Arch.  d.  Heilk.,  1878,  xix,  119. 
•Hindenlang:  Virchow's  Arch.,  1880,  Ixxix,  492. 


368  DISEASE  OF  THE  PANCREAS 

body,  particularly  the  liver,  which  was  slightly  cirrhotic,  and  the  pan- 
creas, and  in  these  organs  found  a  pigment  coiTesponding  to  that  which 
Von  Recklinghausen  subsequently  described  as  haemosiderin. 

Hintze'  has  described  six  cases  which  he  regards  as  examples  of 
haemochromatosis,  but  only  three  agree  in  detail  with  the  description 
which  Von  Recklinghausen  has  given.  Buss^  has  described  a  typical 
case  of  haemochromatosis  associated  with  cirrhosis  of  the  liver  and 
diabetes  mellitus.  Letulle  *  records  two  cases  and  Richardiere '  one 
in  which  with  hypertrophic  cirrhosis  there  was  pigmentation  of  the 
liver,  pancreas,  and  other  organs.  In  these  cases  pigmentation  of  the 
skin  was  apparently  absent.  Osier"  has  recognized  haemochromatosis 
during  life  and  has  confirmed  the  diagnosis  by  demonstration  of  iron- 
containing  pigment  in  a  bit  of  the  bronzed  skin. 

The  following  case,  which  occurred  in  the  practice  of 
Dr.  Thomas  Opie,  is  an  example  of  the  disease: 

Case  XXXV. — The  patient,  male,  white,  aged  fifty-five  years, 
though  never  very  robust,  had  enjoyed  fairly  good  health.  There  was 
no  history  of  alcoholic  excess.  For  several  months  he  had  resided  in 
Porto  Rico,  and  until  six  or  seven  weeks  before  his  death  was  able  to 
continue  his  work  of  surveying.  The  onset  of  his  fatal  illness  occurred 
with  sjTnptoms  of  typhoid  fever.  When  first  seen,  two  weeks  later,  he 
was  evidently  very  ill.  There  was  elevation  of  temperature  and  rose- 
spots  were  present  upon  the  abdomen.  Deep  pigmentation  of  the  skin 
attracted  immediate  attention  and  marked  universal  bronzing  suggested 
Addison's  disease.  Jaundice  was  not  present.  The  urine  at  no  time 
during  the  period  of  observation  contained  sugar;  the  first  examination 
was  made  four  weeks  before  death.  Three  days  before  death  the  urine 
was  clear,  of  deep  amber  color,  and  contained  neither  sugar  nor  albumin. 


205. 


'  Hintze :  Virchow's  Arch.,  1895,  cxxxix,  459. 

'Buss:    Inaug.  Diss.,  Gottingen,  1894. 

'  Letulle :   Bull,  et  mem  Soc.  med.  d'hop.  de  Paris,  1897,  3  s.,  xiv, 

'  Richardiere :  Union  med.,  1895,  3  s.,  lix,  73. 
•Osier:  British  Med.  Jour.,  1899,  ii,  1595. 


HiEMOCHROMATOSIS  369 

The   blood-serum   caused   the    agglutination    of   the   typhoid   bacillus. 
Death  occurred  with  increasing  weakness. 

Autopsy. — The  body  is  that  of  a  very  thin,  sparely-built  man.  The 
skin  over  the  entire  body  is  deeply  pigmented  and  has  a  bronzed  metallic 
hue,  most  marked  upon  the  back  of  the  hands,  about  the  nipples,  and 
upon  the  penis,  where  just  above  the  corona  the  skin  is  dark  brown  in 
color.  The  parietal  peritoneum,  as  well  as  that  of  the  intestines, 
shows  a  varying  degree  of  bluish  discoloration. 

The  muscle  of  the  heart  is  yellowish  brown,  soft,  and  flabby.  Be- 
low the  surface  of  the  right  lung  are  several  small  areas  of  firm  con- 
solidation; the  bronchi  are  intensely  injected. 

The  liver  weighs  2270  Gm.  The  surface  has  a  peculiar  deep 
reddish-brown  color,  resembling  that  of  iron-rust.  The  surface  of  the 
left  lobe,  and  in  less  degree  that  of  the  right  is  superficially  nodular 
and  puckered.  On  section  islands  of  lighter  brown  parenchyma,  repre- 
senting one  or  several  lobules,  are  surrounded  by  fibrous  stroma  of  a 
deeper  brown  color.  Sparsely  scattered  are  opaque,  yellowish- white 
areas,  often  1.5  mm.  across. 

The  spleen,  weighing  700  Gm.,  is  soft;  the  pulp  is  almost  diffluent 
and  has  a  deep  red  color.  The  mucous  membrane  of  the  stomach  shows 
a  deep  greenish-black  discoloration;  along  the  lesser  curvature  there 
are  a  few  areas  of  relatively  normal  yellowish-white  appearance,  but 
elsewhere  the  pig-mentation  is  uniform.  The  duodenum  has  a  greenish- 
black  color  almost  equal  in  intensity  to  that  of  the  stomach.  The 
jejunum  is  less  markedly  pigmented  than  the  duodenum,  while  the 
ileum  is  of  even  lighter  greenish-gray  tint.  Throughout  the  lower  part 
of  the  ileum,  usually  upon  the  iPeyer's  patches,  are  small  roimd  or 
slightly  irregular  ulcers  with  sharp  edges  and  clean  base,  occasionally 
exposing  the  circular  muscle-coat.  The  colon  exhibits  moderate 
gTeenish-gray  discoloration. 

The  pancreas  weighs  170  Gm.  The  organ  is  large,  and  very  firm 
in  consistence.  The  cut  surface  has  a  uniform  deep  chocolate-brown 
color.  The  capsule  contains  much  fat,  and  extending  inward  from  it 
are  septa  of  adipose  and  fibrous  tissue. 

The  cortex  of  the  kidneys  is  red  and  has  a  cloudy  appearance. 
On  section  the  testicles  have  a  light  brown  tint.     In  the  retroperitoneal 

24 


370  DISEASE  OF  THE  PANCREAS 

tissue  near  the  hepatic  vein,  behind  the  stomach,  above  and  below  the 
pancreas,  and  on  either  side  of  the  aorta,  are  enlarged,  moderately  firm 
lymphatic  glands.  On  section  they  exhibit  a  uniform,  brilliant  orange- 
yellow  color.  In  the  gastrohepatic  omentum  are  enlarged  glands  of  a 
similar  nature. 

Anatomical  Diagnosis. — Typhoid  fever;  ulcers  in  the  ileum;  acute 
splenic  tumor;  cloudy  degeneration  of  the  kidneys;  bronchopneumonia. 
Haemochromatosis ;  pigmentation  of  the  liver,  pancreas,  heart,  stomach, 
intestine,  peritoneum,  lymphatic  glands,  skin,  and  testicles;  cirrhosis 
of  the  liver;  chronic  interstitial  pancreatitis. 

Histological  [Examdn^ition. — The  organs  which  show  the  most 
marked  pigmentation  are  the  liver,  pancreas,  heart,  and  gastro-intestinal 
canal. 

There  is  advanced  cirrhosis  of  the  liver;  wide  bands  of  fibrous 
tissue  occupy  from  one-half  to  one-third  of  the  area  of  the  cut  surface. 
These  septa,  which  are  densely  fibrous  and  in  general  poor  in  cells, 
surround  both  the  portal  spaces  and  the  sublobular  veins.  An  immense 
amount  of  yellowish-brown  pigment,  present  in  the  parenchymatous 
cells,  is  deposited  in  the  form  of  brilliant,  brownish-yeUow,  relatively 
coarse  granules,  of  variable  size.  The  endothelial  cells  of  the  capillar- 
ies and  Kiipffer's  cells  contain  granules  of  similar  character.  Pigment 
is  even  more  abundant  in  the  newly-formed  fibrous  tissue.  Here  it 
exists  in  part  as  fine  granules  within  spindle-shaped  cells;  but  the 
greater  quantity  is  not  contained  in  cells.  The  extracellular  pigment 
occurs  in  particles  which  vary  greatly  in  size  and  often  have  a  diameter 
two  or  three  times  that  of  a  red  corpuscle.  This  brownish-yellow  pig- 
ment gives  the  microchemical  reactions  characteristic  of  iron. 

There  is  a  second  less  conspicuous  pigment,  differing  from  that 
already  described  both  in  situation  and  in  character.  In  certain  cells 
of  the  smooth  muscle  and  connective  tissue  which  form  the  media  and 
adventitia  of  both  veins  and  arteries  are  deposited  fine,  pale  yellow 
granules  of  almost  uniform  size.  This  pigment  does  not  give  the 
microchemical  reactions  characteristic  of  iron,  being  imchanged  by 
potassium  ferrocyanide  and  hydrochloric  acid.  In  sections  stained  with 
methylene  blue  such  granules  take  a  blue,  often  bluish-black,  color  and 
become  very  conspicuous  (Buss). 


Fig.  49. — Chronic  interaeinar  pancreatitis  with  hsemochromatosis  showing  deposition  of  haemo- 
siderin  in  cells  of  acini  and  of  i.slands  of  Lanaerhans  and  in  the  interstitial  tissue. 


HEMOCHROMATOSIS  371 

Interstitial  tissue  of  the  pancreas  is  much  increased  (Fig.  49 j; 
in  many  places  it  defines  the  lobules,  but,  as  a  rule,  it  is  diffusely  dis- 
tributed, occurring  as  irregular  masses  and  strands  separating  small 
groups  of  acini  or  individual  acini.  Yellowish-brown  pigment,  giving 
the  mierochemical  reactions  of  iron,  is  abundant  both  in  the  glandular- 
cells  and  in  the  interstitial  tissue.  The  cells  of  the  acini  contain  this 
pigment  in  varying  amount;  here  and  there  are  acini  of  which  the  cells 
are  distended  and  almost  entirely  replaced  by  pigment-granules.  Such 
cells  often  show  evidence  of  degeneration;  at  times  the  nucleus  has  an 
irregular  outline,  and  stains  very  palely,  while  in  many  instances  no 
nucleus  is  demonstrable.  The  fibrous  tissue  replacing  the  disintegrated 
cells  contains  free  granules  of  pigment,  which  are  larger  and  more 
globular  than  those  within  the  cells. 

Islands  of  Langerhans  are  fairly  abundant  throughout  the  organ, 
but  are  most  numerous  in  sections  from  the  tail.  They  are  constantly 
surrounded  by  a  small  area  of  fibrous  tissue  containing  pigment  in 
considerable  quantity.  Embedded  in  stroma,  they  no  longer  possess 
a  regular  round  or  oval  outline,  but  are  irregular  in  shape  and  are 
penetrated  by  thickened  fibrous  strands  which  follow  the  capillary 
vessels.  The  cells,  foiining  compact  columns,  contain  numerous  gran- 
ules of  pigTQent  which,  when  least  abundant,  are  situated  in  the  part 
of  the  cell  most  distant  from  the  capillaries,  and  hence  tend  to  occupy 
the  mid-line  of  the  cell-columns.  The  cells  of  the  interacinar  islands 
usually  contain  much  more  pigment  than  those  of  the  adjacent  acini. 
In  preparations  hardened  in  Fleming's  solution  fat  can  be  found  in 
many  of  the  secreting  cells,  but  it  is  constantly  present  in  the  cells  of 
the  interacinar  islets. 

Deposition  of  pigment  and  the  associated  histological  lesions  in  the 
skin,  gastro-intestinal  tract,  heart,  spleen,  kidneys,  adrenals,  and 
lymphatic  glands,  though  of  considerable  interest,  are  not  pertinent 
to  the  present  study,  and  will  be  omitted. 

Bronzed  Diabetes. — A  condition  closely  related  to 
haBmochromatosis  of  Von  Eecklinghausen  has  been  stud- 
ied particularly  by  French  writers.    In  1882  Hanot  and 


372  DISEASE  OF  THE  PANCREAS 

Chauffard^^  described  two  cases  of  diabetes  mellitus 
associated  clinically  with  hypertrophic  cirrhosis  of  the 
liver  and  bronze-like  pigTaentation  of  the  skin.  In  one 
case,  more  carefully  studied,  the  liver  and  pancreas  pre- 
sented a  brown  pigmentation  and  were  the  seat  of  ad- 
vanced chronic  interstitial  inflammation,  both  parenchy- 
matous cells  and  interstitial  tissue  containing  masses  of 
pigment  granules.  Letulle  ^^  several  years  later  re- 
ported two  cases  of  a  similar  nature.  In  a  second  com- 
munication Hanot,^^  in  conjunction  with  Schachmann, 
recorded  a  fifth  case  and  reviewed  those  previously  pub- 
lished. He  believed  that  the  observations  which  had 
been  made  established  the  existence  of  a  new  form  of  cir- 
rhosis— cirrhose  pigmentaire  diabetique,  and  of  a  new 
clinical  condition — diabete  bronze. 

The  designation  "diabete  bronze"  has  been  accepted, 
but  not  without  protest.  Bronzing  of  the  skin  is  not  a 
constant  phenomenon,  and  has  been  absent  in  one  case 
of  Letulle,  in  the  case  of  Hanot  and  Schachmann,  and  in 
a  CELse  recorded  by  Brault  and  Galliard.^* 

The  symptoms  and  pathological  findings  in  the  re- 
corded cases  of  so-called  bronzed  diabetes  have  been  very 
constant.  Clinically,  there  is  rapidly  fatal  diabetes  mel- 
litus, associated  with  cirrhosis  of  the  liver,  which  is 
usually  hypertrophic.  Bronzing  of  the  skin  is  not  con- 
stant, but  has  been  present  in  a  majority  of  the  cases. 
In  two  cases  of  Futcher^^  diagnosis  was  confinned  by 


"  Hanot  and  Chauffard :  Rev.  de  med.,  1882,  ii,  385. 

"  Loc.  cit. 

"Hanot  and  Schachmann:    Arch,  de  physiol.,  1886,  3  s.,  vii,  50. 

"  Brault  and  Galliard :  Arch.  gen.  de  med.,  1888,  i,  38. 

"Futcher:  American  Jour,  of  the  Med.  Soien.,  1907,  cxxxiii,  78. 


HEMOCHROMATOSIS  373 

demonstration  of  iron-containing  pigment  in  sections 
prepared  from  bits  of  skin.  At  autopsy  there  is  deep 
pigmentation  of  the  liver  and  pancreas,  associated  with 
cirrhosis,  and  in  cases  carefully  examined,  interstitial 
pancreatitis.  Ochre-colored  pigment  giving  the  micro- 
chemical  reactions  of  iron  is  present  in  the  parenchy- 
matous cells  of  the  liver,  pancreas,  and  other  glands, 
in  the  muscle-fibres  of  the  heart,  in  the  interstitial  tissue 
of  these  organs,  and  in  the  lymphatic  glands. 

Only  one  recorded  instance  of  haemochromatosis  (the 
case  of  Abbott  ^^),  or  of  bronzed  diabetes,  has  occurred 
in  the  female.  The  age  of  the  individuals  affected  with 
bronzed  diabetes  has  varied  between  thirty-three  and 
sixty-two  years,  the  greatest  number  of  cases  occurring  in 
the  fourth  and  fifth  decades.  The  cases  of  simple  haemo- 
chromatosis fall  within  these  limits.  It  has  been  believed 
that  the  disease  with  diabetes  is  more  common  in  France 
than  elsewhere,  for  of  twenty-four  cases  seventeen  have 
been  observed  in  that  country.  Simple  haemochroma- 
tosis, however,  has  been  described  more  frequently  by 
German  writers.  Among  two  hundred  and  fifty-six 
cases  of  diabetes  treated  in  the  Johns  Hopkins  Hospital, 
Futcher  found  two  instances  of  bronzed  diabetes. 

The  pathogenesis  of  the  condition  has  been  the  subject 
of  much  speculation.  Hanot  has  maintained  that  the 
primary  etiological  factor  is  diabetes  mellitus;  diabetes 
with  endarteritis,  which  he  has  found  constant  in  his 
cases,  disturbs  the  nutrition  of  the  liver  cells,  and,  he 
thinks,  alters  pigment  metabolism  so  that  pigment  is 
deposited.     Excess  of  the  pigment,  he  suggests,  is  trans- 

"  Abbott:  Trans,  of  the  Path.  Soc.  of  London,  1900,  li,  66. 


374  DISEASE  OF  THE  PANCREAS 

ported,  possibly  in  the  form  of  emboli,  from  the  liver 
to  the  other  organs.  Letulle  thinks  that  the  pigment  is 
formed  under  the  influence  of  hyperglycaemia  within  the 
cells  in  which  it  is  found.  Brault  and  Galliard,  Hernan- 
dez,^'^ Mosse,^^  Rendu  and  De  Massary,^^  give  prominence 
to  diabetes  as  the  important  factor  in  producing  pigmen- 
tation. 

A  second  smaller  group  of  writers  think  that  pigmen- 
tation is  produced  by  some  primary  disease  of  the  blood. 
P.  Marie  2"  thinks  that  some  change  causes  dissolution 
of  haemoglobin,  which  is  transformed  by  various  cells 
of  the  body  into  pigment  and  is  deposited  in  these  cells. 
The  pigment  in  turn  causes  degeneration  and  destruction 
of  the  cells  in  which  it  accumulates,  and  in  consequence 
chronic  interstitial  inflammation  of  various  organs,  nota- 
bly the  liver;  and  if,  Marie  says,  it  should  be  necessary 
to  compare  the  condition  with  any  other,  he  would  turn 
his  attention  to  jjancreatic  diabetes.  Acard,^!  Dutour- 
ier,22  and  Jeanselme  ^3  reiterate  this  view,  and  suggest 
that  diabetes  is  only  an  accessory  phenomenon  which 
appears  with  a  certain  degree  of  chronic  interstitial  pan- 
creatitis. Anschiitz-^  has  convinced  himself  that  the 
associated  diabetes  finds  its  cause  in  chronic  interstitial 
pancreatitis,  which,  like  the  accompanying  cirrhosis  of 

"  Hernandez :  Thesis,  Montpelier,  1892. 

"  Mosse :  Cong,  f  ran^ais  de  med.,  1894.    Paris,  1895,  i,  776. 

"Rendu  and  De  Massary:  Bull,  et  mem.,  Soe.  d.  hop.  de  Paris, 
1897,  s.  3,  xiv,  163. 

"  Marie,  P. :  Sem.  med.,  1895,  xv,  229. 

"  Acard :  Thesis,  Paris,  1895. 

"Dutourier:  Thesis,  Paris,  1895. 

"  Jeansehne:  Bull,  et  mem.  Soc.  med.  d.  hop.  de  Paris,  1897,  3  s., 
xiv,  179. 

"  Anschutz :  Deutsches  Arch,  f .  klin.  Med.,  1899,  Ixii,  411. 


HEMOCHROMATOSIS  375 

the  liver,  is,  he  believes,  a  manifestation  of  some  under- 
lying condition. 

French  writers  who  described  cases  of  "diabete 
bronze"  did  not  identify  the  pig-mentation  with  the  haemo- 
chromatosis  of  Von  Eecklinghausen.  Hernandez  demon- 
strated that  the  brownish-yellow  granules  found  by  him 
in  the  epithelial  cells  of  the  liver,  pancreas,  and  kidney, 
in  the  muscle  cells  of  the  heart,  in  the  connective  tissue 
of  these  organs,  and  in  the  lymphatic  glands,  gave  the 
microchemical  reactions  known  to  be  characteristic  of 
iron.  In  this  case  and  in  subsequent  cases  the  yellowish- 
brown  pigment  agrees  in  morphology  and  in  location  with 
the  haemosiderin  of  Von  Eecklinghausen. 

Buss  reported  a  case  of  diabetes  associated  with  cir- 
rhosis of  the  liver  and  chronic  pancreatitis  with  general 
haemochromatosis.  He  found  not  only  the  iron-contain- 
ing but  the  iron-free  pigment  in  locations  corresponding 
to  those  mentioned  by  Von  Eecklinghausen. 

The  case  described  in  the  present  chapter  holds  a 
position  intermediate  between  haemochromatosis  and  so- 
called  bronzed  diabetes.  Associated  with  haemochroma- 
tosis there  is  bronzing  of  the  skin,  cirrhosis  of  the  liver 
of  advanced  grade,  and  chronic  interstitial  pancreatitis. 
Diabetes,  however,  has  not  been  present.  It  is  evident 
that  the  generalized  pigmentation  of  bronzed  diabetes  is 
the  haemochromatosis  of  Von  Eecklinghausen. 

Etiology  of  Hcemochromatosis. — The  iron-containing 
pigment  deposited  in  the  liver  and  other  organs  is  doubt- 
less derived  from  the  haemoglobin  of  the  blood.  With 
pernicious  anaemia  there  is  destruction  of  blood,  and  iron 
is  deposited  in  the  liver  and  other  organs,  but  pigmen- 
tation of  the  character  under  consideration  is  not  found. 


376  DISEASE  OF  THE  PAN'CREAS 

A  considerable  proportion  of  the  cases,  both  of  simple 
haBmochromatosis  and  of  haBmochromatosis  associated 
with  diabetes,  have  been  accompanied  by  conditions  which 
involve  active  destruction  of  the  red  blood-corpnscles. 
Hindenlang's  case  of  general  pigmentation,  almost  cer- 
tainly one  of  haemochromatosis,  was  associated  with  mor- 
bus maculosiis  Werlhoffi.  In  four  other  cases  purpuric 
eruptions  have  been  observed.  In  several  instances  there 
have  been  local  hemorrhages;  in  the  case  of  Buss,  for 
example,  there  have  been  hemorrhagic  pleurisy,  peri- 
tonitis, and  pachymeningitis.  Haematuria  has  occurred 
in  a  case  of  Hernandez  and  hemoglobinuria  has  been  ob- 
served by  Hess  and  Zurhelle.-^  In  a  large  number  of 
cases  local  hemorrhages  have  not  been  demonstrable. 

Discovery  of  phagocytosis  of  red  blood-corpuscles 
by  parenchymatous  ceUs  of  various  organs,  according  to 
Rossle,26  explains  the  pathogenesis  of  haemochromatosis. 
A  man,  thirty-nine  years  of  age,  who  during  three  years 
had  repeatedly  suffered  with  slight  jaundice,  died  after 
an  illness  of  eight  days;  there  was  fever,  jaundice,  cya- 
nosis and  oedema  of  the  legs.  Rossle  found  haemochro- 
matosis ;  the  liver  was  pigmented,  cirrhotic,  and  atrophic. 
Microscopic  examination  showed  that  cells  of  the  liver 
had  acted  as  phagocytes  and  had  taken  red  blood-cor- 
pnscles, often  from  20  to  25,  into  their  substance.  Cor- 
puscles had  undergone  changes  as  the  result  of  ingestion, 
and  many  had  lost  their  peculiar  staining  properties; 
transformation  into  granules  and  clumps  of  pigment  had 
occurred. 

"  Hess  and  Zurhelle :  Zeit.  f .  klin.  Med.,  1905,  Ivii,  344. 
"Rossle:  Ziegler's  Beitrage,  1907,  xli,  181. 


HEMOCHROMATOSIS  377 

Eossle  believes  that  such  phagocytosis  of  red  blood- 
corpuscles  is  possible  because  capillaries  in  localized 
areas  have  undergone  disintegration;  red  blood-cor- 
puscles are  in  contact  with  liver  cells,  but  it  has  been 
uncertain  if  mere  contact  is  sufficient  to  explain  phago- 
cytosis. At  the  periphery  of  foci  in  which  disintegration 
of  the  endothelial  cells  had  occurred,  regeneration  of 
capillaries  with  accompanying  formation  of  fibrous  tissue 
was  in  progress.  Phagocytosis  of  red  corpuscles  by 
parenchymatous  cells  was  found  in  the  pancreas  and  in 
the  kidney.  Eossle  thinks  that  disintegTation  of  en- 
dothelial cells  has  been  caused  by  the  presence  of  a 
lanceolate  streptococcus  found  in  sections  of  various 
organs,  but  unidentified  by  culture. 

Some  of  those  who  have  studied  cases  of  bronzed 
diabetes  have  regarded  diabetes  as  the  essential  etio- 
logical factor.  Upon  an  insufficient  basis  active  blood 
destruction  has  been  assumed  to  be  a  result  of  the  diabetic 
condition.  In  the  ordinary  form  of  diabetes,  ZalesM^' 
and  Kretz  -^  have  found  no  accumulation  of  iron  in  the 
liver  or  other  organs.  There  is,  on  the  contrary,  reason 
to  believe  that  diabetes  is  secondary  to  haemochromatosis. 

Relation  of  Hcemochroynatosis  to  Chronic  Interstitial 
Inflammation. — Study  of  the  process  of  pigment  accumu- 
lation in  widely  separated  organs — for  example,  the  liver. 
pancreas,  and  adrenal  glands — demonstrates  the  site  of 
its  formation.  When  pig-ment  is  in  moderate  Cjuantity, 
it  occurs  as  relatively  fine  round  granules  occupying  that 
part  of  the  cell  most  distant  from  the  capillaries — that  is, 

'"'  Zaleski :  TirchoVs  Arch..  1SS6.  civ,  91. 

"■"  Kvetz:  Beit.  z.  klin.  Med.  u.  Chir.,  Hft.  st,  Yienna,  1896;  Cent.  f. 
allg.  Path.  u.  path.  Anat..  1S97,  viii,  620. 


378  DISEASE  OF  THE  PANCREAS 

in  acinous  glands,  the  part  next  the  lumen.  With  greater 
accumulation  the  whole  cell-body  contains  pigment  gran- 
ules, and  finally  almost  the  entire  protoplasm  is  replaced 
by  them.  Changes  at  the  same  time  may  be  observed 
in  the  nucleus  of  the  cell.  It  becomes  smaller,  its  outline 
often  becomes  irregular,  and  it  assumes  a  shrivelled  ap- 
pearance. Masses  of  pigment  with  no  nucleus  may  re- 
tain the  cell  outline.  Finally  the  shape  of  a  cell  is  lost 
and  a  clump  of  pigment  particles  lies  free  in  the  tissue. 

The  process  observed  in  the  liver  takes  place  in  the 
pancreas  and  adrenal  gland,  in  the  muscle  cells  of  the 
heart,  and  in  many  other  tissues.  It  is  improbable  that 
the  pigment  found  in  various  organs  is  transported  as 
emboli  or  in  phagocytic  cells  from  the  liver;  Margain 
has  found  particles  of  pigment  in  the  circulating  blood. 
The  pigment  is  doubtless  elaborated  by  the  cells  in  which 
it  is  found  from  iron-containing  material  derived  from 
haemoglobin;  the  observation  of  Rossle  suggests  that 
phagocytosis  has  a  part  in  the  process. 

Degenerate  parenchymatous  cells  overloaded  with  pig- 
ment are  very  abundant  in  the  case  which  I  have  studied. 
Such  degeneration  is  an  important  factor  in  the  produc- 
tion of  chronic  interstitial  inflammation;  fibrous  stroma 
replaces  the  cells  which  are  destroyed.  In  the  liver 
newly  formed  fibrous  tissue  invades  the  lobule  along  the 
central  vein,  and  in  places  sends  out  fine  radiating  bands 
along  the  capillaries  between  the  columns  of  the  liver 
cells.  The  fibrous  tissue  about  the  central  vein  and  be- 
tween the  lobules  contains  large  quantities  of  pigment, 
which  is  for  the  most  part  extracellular,  because  the  cells 
in  which  it  was  formed  have  undergone  degeneraiion. 
When  pigment  is  massed  in  large  quantity,  there  is 
usually  accumulation  of  cells  about  it.    In  general  the 


h^:mochromatosis  379 

interlobular  tissue  is  poor  in  cells,  but  in  such  areas  pro- 
liferation is  indicated  by  the  presence  of  small  round 
cells.  Two  factors  are,  I  believe,  active  in  producing 
sclerosis:  (1)  Pigmentary  degeneration  of  the  parenchy- 
matous cells;  (2)  irritation  produced  by  the  presence  of 
the  pigTuent  in  the  interstitial  tissue. 

Relation  of  Hcemochromatosis  to  Diabetes. — In  the 
case  I  have  described  the  pancreas  next  to  the  liver  is  the 
organ  most  conspicuously  pigmented.  Extreme  pigmen- 
tation and  consequent  degeneration  of  parenchymatous 
cells  has  occurred,  and  the  organ  is  the  seat  of  chronic 
interstitial  inflammation  of  the  inter  acinar  type. 

In  reports  of  cases  of  bronzed  diabetes,  accompanied 
by  a  record  of  the  microscopic  appearance  of  the  pancreas, 
chronic  interstitial  pancreatitis  has  been  described.  The 
gland  has  been  usually  described  as  voluminous,  enlarged, 
or  normal  in  size.  In  seven  cases  in  which  the  weight 
is  recorded,  the  mean  of  the  figures  given  is  125.7  Gm., 
about  one-half  greater  than  the  normal  weight  of  the 
organ.  The  average  weight  of  the  liver  recorded  in 
thirteen  cases  of  bronzed  diabetes  has  been  2497  Gm. 
Both  cirrhosis  and  chronic  pancreatitis  are  associated 
with  hypertrophy. 

In  my  case  of  haemochromatosis  without  diabetes  the 
pancreas  has  weighed  170  Gm.,  almost  twice  the  normal 
weight,  and  is  the  seat  of  interacinar  inflammation  of 
moderate  intensity.  The  lesion  affects  primarily  the 
parenchymatous  cells,  and  the  newly  formed  fibrous  tis- 
sue is  diffusely  distributed  and  bears  no  constant  rela- 
tion to  the  lobules.  Alterations  of  the  islands  of 
Langerhans  have  been  as  follows :  Pigment  is  abundant 
in  the  cells,  and  tends  to  accumulate  in  that  part  which 
is   most   distant   from   the    capillaries.     The   island   is 


380  DISEASE  OF  THE  PANCREAS 

usually  embedded  in  a  capsule-like  mass  of  fibrous  tissue 
containing  pigment  granules,  and  strands  of  similar 
tissue  often  penetrate  the  island,  following  its  capillaries. 
The  lesion  is  little  advanced,  and  has  caused  such  incom- 
plete destruction  of  the  islands  of  Langerhans  that  dia- 
betes has  not  ensued.  The  individual  had  been  in  good 
health  until  attacked  by  typhoid  fever.  When,  as  in  this 
case,  haemochromatosis  without  diabetes  has  been  ob- 
served at  autopsy,  death  has  been  due  to  some  intercur- 
rent affection  having  no  apparent  relation  to  the  ante- 
cedent disease.  The  fatal  illness  in  most  instances  begins 
with  symptoms  of  diabetes.  In  the  present  instance 
typhoid  fever  caused  death  of  the  individual  before 
chronic  interstitial  pancreatitis  had  reached  a  grade  of 
intensity  sufficient  to  produce  glycosuria,  and  haemochro- 
matosis had  been  prevented  from  reaching  its  usual  ter- 
mination— diabetes. 

In  the  pancreas  in  an  individual  with  haemochroma- 
tosis and  diabetes  Beattie-^  found  few  islands  of  Lan- 
gerhans. They  were  surrounded  by  a  capsule  of  dense 
fibrous  tissue  containing  pigment ;  their  cells  were  irregu- 
lar in  shape,  and  the  nuclei  stained  faintly.  Beattie 
thought  that  fibrous  nodules  which  he  found  had  per- 
haps replaced  islands  of  Langerhans.  Hess  and  Zur- 
helle  described  two  cases  of  haemochromatosis  with 
diabetes ;  in  one  instance  no  islands  of  Langerhans  could 
be  found,  and  in  the  other  only  one  of  these  structures 
was  recognizable. 

Cecil  has  described  the  pancreas  from  the  two  follow- 
ing cases  of  bronzed  diabetes. 

"•Beattie:    Jour,  of  Path,  and  Bact.,  1903,  ix,  117. 


m 

V     ;     j^ 

• 

._^#     *?|g       * 

,v  ;'^^^  •  •'■ 

•>           .:     4         V- 

<« 

.  ^      V,^ 

•Vr:                  '■          ,     /' 

' 

■   "^^    "^^ 

^' 

'-"";■ 

fek" 

i^.%.X   '»i' 

Fig.  50. — Island  of  Langerhans  from  case  of  hemochromatosis  with  diabetes  mellitus   showing 
deposition  of  hoemosiderin . 


HEMOCHROMATOSIS  381 

A  man,  thirty-seven  years  of  age,  admitted  to  the  Johns  Hopkins 
Hospital,  had  suffered  with  diabetes  during  nine  months;  the  urine 
contained  6.5  per  cent,  of  glucose.  There  was  pigmentation  of  the 
skin  and  ascites.  Death  occurred  with  coma.  The  liver  was  cirrhotic 
and  pigmented;  the  skin,  heart  muscle  and  lymphatic  glands  were 
pigmented.  The  pancreas,  which  weighed  150  Gm.,  was  firm,  brown, 
and  penetrated  by  fat.  A  section  of  the  pancreas,  obtained  through 
the  kindness  of  Dr.  W.  G.  MacCallum,  shows  increase  of  both  inter- 
lobular and  interacinar  connective  tissue  in  which  there  is  abundant 
iron-containing  pigment.  Many  of  the  acinar  cells  are  loaded  with 
pigment.  Few  islands  of  Langerhans  can  be  found;  they  are  very 
small,  and  are  surrounded  by  a  thickened  capsule  of  fibrous  tissue 
containing  pigment.     Cells  of  the  interacinar  islands  contain  pigment. 

A  man,  aged  forty-three  years,  was  admitted  to  the  Massachusetts 
General  Hospital  with  diabetes  mellitus;  there  was  3  per  cent,  of  sugar 
in  the  urine.  Coma  preceded  death.  The  liver  was  cirrhotic  and 
pigmented;  the  pancreas  was  dark  brown  in  color.  Sections  of  the 
pancreas,  obtained  through  the  kindness  of  Dr.  James  H.  Wright, 
showed  the  presence  of  lipomatosis,  interacinar  pancreatitis,  and 
deposition  of  pigment  in  acinar  cells  and  stroma.  Islands  of  Langer- 
hans were  fairly  numerous,  and  normal  in  size;  many  of  them  were 
surrounded  by  dense  fibrous  capsules,  and  about  the  capillaries  was 
thickened  stroma.  Many  of  cells  of  the  islands  of  Langerhans  were 
distended  with  pigment  (Fig.  50) ;  their  nuclei  stained  poorly.  The 
arteries  of  the  gland  were  somewhat  thickened. 

Haemochromatosis,  a  disease  sui  generis,  is  charac- 
terized by  wide-spread  deposition  of  pigment  in  various 
tissues  of  the  body.  It  is  associated  with  chronic  inter- 
stitial inflammation,  notably  of  the  liver  and  pancreas. 
Parenchymatous  cells  imdergo  pigmentation  and  degen- 
eration, and  fibrous  stroma  fills  the  defect  thus  produced. 
In  the  pancreas  chronic  inflammation  is  of  the  inter- 
acinar type,  and  the  islands  of  Langerhans  are  impli- 
cated in  the  lesion.  When  interacinar  pancreatitis  has 
reached  a  certain  grade  of  intensity,  diabetes  mellitus 
ensues. 


INDEX 


Aberrant    pancreatic   tissue    in    pa- 
pillae, 38 
Accessory  pancreas,  definition  of,  30 
mesentery  in,  36,  43 
omentum,  in,  37,  43 
origin  of,  40 
tumors  from,  38 
umbilicus,  of,  36 
Acini,  structure  of,  56 

changes  with  secretion  in,  57 
Acne  pancreatica,  267 
Acromegaly,  357 
Activator  of  pancreas,  114 
Acute  hemorrhagic  pancreatitis  (see 
Hemorrhagic    necrosis    of   the 
pancreas) 
interstitial  pancreatitis,  200 
pancreatitis,  etiology  of,  201 
pathology  of,  203 
varieties  of,  118,  200 
Adenocarcinoma,  289 
Adenocystoma  papilliferum,  269,  288 
Adenoma,  290 
Adenoma-hke  hypertrophy  of  islands 

of  Langerhans,  342 
Adrenal,   influence  on  pancreas  of, 

115,  359 
Adrenalin,  106 
Alcohol,  238,  351 
Alimentary  glycosuria,  104,  108,  263, 

283,  293,  353,  363 
Amyloid  degeneration,  313,  348 
Amylopsin,  85 
Angio-sarcoma,  291 
Annular  pancreas,  29 
Anomalies  of  pancreas,  29 
Anti-trypsin,  82 
Arterial  sclerosis,  233,  245,  313,  333, 

350,  362 
Atrophy  of  the  pancreas,  granular, 
333 
simple,  334 
Autolytic     products     of     pancreas, 

toxicity  of,  166 
Azotorrhoea,  90,  263 

B 

Bile  duct,  carcinoma  of  pancreas  and, 

294 
pancreas,  and,  21 
pancreatic  ducts,  and,  3,  10, 

14 


Bile    causing    hemorrhagic    necrosis 

of  pancreas,  140,  193 
papilla,  aberrant  pancreatic^tis- 

sue  in,  38 
Blood-vessels  of  pancreas,  22,  54,^65 
Bronzed  diabetes,  137 


C 

Calculi  of  pancreas,  composition  of, 
257 
cysts,  and,  261 
diagnosis  of,  264 
formation  of,  261 
interstitial     pancreatitis, 

with,  226 
incidence  of,  257 
operation  for,  265 
pathology  of,  257 
steatorrhoea,  with,  95 
symptoms  of,  262 
treatment  of,  264 
Cammidge's  reaction,  99 
Carbohydrates,  absorption  of,  95 
Carcinoma     of     pancreas,     chronic 
interstial     pancreatitis, 
and,  228,  291 
colloid,  288 
diagnosis  of,  295 
incidence  of,  288 
metastases  from,  289,  292 
symptoms  of,  129 
treatment  of,  296 
Catarrhal  pancreatitis,  201 
Centro-acinar  cells,  50,  57 
Chronic  interactnar  pancreatitis,  213, 
219 
arterial  sclerosis,  and, 

235,  351 
diabetes  mellitus,  and, 

334 
symptoms  of,  248 
interlobular  pancreatitis,  213 
ascending    infection, 

and,  218,  229 
duct-obstruction,  and, 

213,  225 
symptoms  of,  247 
interstitial    pancreatitis,    acces- 
sory pancreas,  of,  37 
acromegaly,  and,  358 
alcohol,  and,  238 
arterial  sclerosis,    and, 
233 

383 


384 


INDEX 


Chronic  interstitial    pancreatitis. — 
Continued. 

azotorrhoea,  with,    90, 

96 
calculi,  and,  226 
carcinoma,  and,  291 
cat,  in,  52 
causing    malignant 

growth,  228 
cholelithiasis    causing, 

226 
chronic     passive    con- 
gestion, and,  235 
cirrhosis,  and,  239,  372, 

377 
cyst,  and,  268 
etiology  of,  224 
hsemochromatosis,  and, 

377 
islands  of  Langerhans, 
and,   210,   214,   216, 
221,  380 
symptoms  of,  243 
syphilis,  and,  238 
tuberculosis,  and,  237 
varieties  of,  209,  210 
vomiting,  and,  230 
Cirrhose  pigmentaire  diabetique,  372 
Cirrhosis  of  the  liver,  239,  245,  372, 

377 
Cohc,  pancreatic,  264,  292 
Cyst  of  pancreas,  apoplectic,  270 
aspiration  of,  285 
calculi,  and,  261 
contents  of,  272 
diagnosis  of,  283 
hemorrhagic  necrosis,  and, 

271 
operation  for,  284 
position  of,  273 
proliferation,  268 
retention,  266 
rupture  of,  279 
symptoms  of,  281 
traumatic,  270,  283 
Cystadenoma,  268,  283 


D 


Development  of  the  pancreas,  4 
DiabSte  bronz^,  365,  372 
Diabetes  mellitus,  acromegaly,  and, 
357 
adrenal  lesion,  and,  359 
arterial  sclerosis,  and,    350, 

362 
atrophy  of  pancreas,  with, 
333,  334 


Diabetes  mellitus. — Continued. 

azotorrhoea,  with,  90,  96 
calculi  causing,  262,  331 
carcinoma,    and,  291,  293, 

330 
chronic    interstitial    pan- 
creatitis, and,  331,  361, 

377 
cirrhosis  of  liver,  with,  352, 

372,  377 
cyst,  and,  282 
diagnosis  of  pancreatic,  360 
disease  of  central  nervous 

system,  and,  353 
exophthalmic    goitre,    and, 

355 
experimental,  107 
hsemochromatosis,  and,  379 
hemorrhagic      necrosis      of 

pancreas,  and,  170,  329 
hypertrophy   of   islands   of 

Langerhans,  with,  341 
islands  of  Langerhans,  and, 

307,  322,  324,  341,  344, 

346,  380 
lesions  of  fourth  ventricle, 

with,  354 
myxcedema,  357 
normal  pancreas,  with,  318, 

322,  349 
pancreatic,  317 
renal,  354 

small  pancreas,  with,  337 
suppurative  pancreas,  and, 

329 
Diabetic  puncture,  104 
Diverticula  in  contact   with  acces- 
sory pancreas,  44 
with  pancreas,  46 
Diverticulum  of  Vater,  13,  147 
carcinoma  of,  203,  215 
gall-stone  in,  133,  143,  191, 

202,  208,  227 
Duct-obstruction,  diabetes  mellitus, 
and, 331 
lesion  caused  by,  213,  225 
Duct  of  Santorini,  2,  16 
Duct  of  Wirsung,  2,  55 
Ducts  of  pancreas,  discovery  of,  2 
histology  of,  55 
ligation  of,  89,  92,  108,  185, 

217,  345  _ 
in  lower  animals,  3 
necrosis    of    pancreas    and 

anomalies  of,  151 
parenchyma,  and,  17 
regeneration  of,  42 
variation  of,  7 


INDEX 


385 


Duodenal   contents   causing   hemor- 
rhagic  necrosis    of   pancreas, 
150 
papilla,      aberrant      pancreatic 
tissue  in,  38 

E 

Emaciation,  283,  292 
Embryology  of  pancreas  (see  Devel- 
opment) 
Entero kinase,  83,  151 
Enzymes,  in  cysts  of  pancreas,  272 

hemorrhagic    necrosis    of    pan- 
creas, and,  121,  147,  161,  166 

therapeutic  use  of  pancreatic,  95 
Epithelioma  cysticum,  269,  288 
Etherial  sulphates  in  urine,  98 
Exophthalmic  goitre,  355 

F 

Faeces,  voluminous,  95,  293 
Fat,  absorption  of,  88,  92 

faeces,  in  (see  Steatorrhoea) 
necrosis,     accessory     pancreas, 

and,  37 
bacteriology  of,  180 
Benda's  copper  acetate  re- 
action for,  179 
calculi,  and,  206 
chemistry  of,  178 
chronic    pancreatitis,    and, 

188,  192 
clinical  significance  of,  197 
corpulence,  and,  178 
disappearance  of,  180 
disseminated,  176 
duct-occlusion,  and,  190 
experimental,  185 
hemorrhagic      necrosis      of 

pancreas,  and,  119,  126, 

157,   159,  173,  183,  193, 

198 
historical  data  concerning, 

176 
lower  animals,  in,  177 
pancreas,  and,  181 
pancreatin,  and,  184 
parapancreatic,  195 
pericardial,  177,  186 
recovery,  with,  199 
self-digestion    of    pancreas, 

and,  86 
subcutaneous,      177,      178, 

186,  189,  197 
suppurative       pancreatitis, 

and,  120,  205 
without   pancreatic   lesion, 


Fat-splitting   enzyme,    fat    necrosis, 
and,  184,  187,  198 
urine,  in,  198 
Fatty  degeneration,  299 
Fistula,  pancreatic,  286 

experimental  pancreatic,  77,  89 

G 

Gall-stones,  calculi  of  pancreas,  and, 

258 
cysts,  and,  268 

diverticulum  of  Vater,  in,  133, 
143,  191,  202,  208,  227 
Gangrenous  pancreatitis,  119 
Gastroptosis,  24 
Glucose  in  blood,  102,  107 
Glycosuria,  adrenalin,  and,  106 
disappearance  of,  106,  348 
extirpation  of  duodenum,  and, 

108 
hemorrhagic    necrosis    of    pan- 
creas, and, 170 
injury  to  nervous  system,  and, 

105 
suppurative    pancreatitis,    and, 

206 
toxic  substances,  and,  106 
Glycogen,  103 
Glycolytic  enzyme,  112 
Gumma  of  pancreas,  254,  255 

H 

Hsemochromatosis,  case  of,  368 

chronic  interstitial  pancreatitis, 

and,  377 
definition  of,  365 
diabetes  mellitus,  and,  353 
etiology  of,  375 

islands  of  Langerhans,  and,  380 
pathogenesis  of,  373 
symptoms  of,  372 
Hsemofuscin,  366 
Haemosiderin,  366 
Hemorrhage,  pancreatic,  122 
Hemorrhagic    necrosis   of   pancreas, 
with    accumulation 
of  fluid  within  lesser 
peritoneal     cavity, 
163 
anomalies  of  ducts  and, 

151 
bacteriology  of,  128 
bile  producing,  140 
cholelithiasis,  and,  129, 

143,  148,  167,  174 
cyst,  and,  271 
definition  of,  118 


386 


INDEX 


Hemorrhagic  necrosis  of  pancreas. — 
Continued. 

duodenal     contents, 

and,  150 
etiology  of,  127 
experimental,  124,  160 
histology  of,  159 
injury,  and,  156 
leucocytosis,  with,  145, 

170 
operation  for,  172 
pathology  of,  158 
perforation   of  gastro- 
intestinal tract  with, 
164 
recurrent,  171 
relation  to     inflamma- 
tion of,  120 
retroperitoneal  erosion, 

with,  164,  169,  174 
sex,  and,  150,  163 
stage   of   gangrene   of, 

162,   168,  173 
suppuration  with,  168 
symptoms  of,  164 
treatment  of,  171 
Histogenesis  of  pancreas,  66 
Histology  of  pancreas,  50 
Hyaline  degeneration,  300,  310 

thrombosis  of  capillaries,  160 
Hypertrophy  of  pancreas,  334,  358, 
379 

I 

Inanition  and  islands  of  Langerhans, 

72 
Indican  in  urine,  98 
Infantilism,  pancreatic,  97 
Injury  of  pancreas,  25,  156,  270,  283 
Interlobular  fissure  of  pancreas,  20 
Internal  secretion,  75,  112,  117 
Intestinal      obstruction,      accessory 
pancreas,  and,  45,  197 
hemorrhagic      necrosis      of 
pancreas,  and,  167,  173 
Islands  of  Langerhans,  acini,  and,  69, 
72 
adenoma  of,  290 
amyloid  degeneration,  and, 

313,  348 
blood-vessels  of,  51,  65 
cells  of,  64 

chronic  interstitial  pancrea- 
titis, and,  210,  214,  216, 
221,  242 
congenital  syphilis,  and,  251 
diabetes  mellitus,  and,  307, 
324,  330,  331,  334,  338, 
361 


Islands  of  Langerhans. — Continued. 

diminution  in  number  of, 
338 

experimental  study  of,  344 

fatty  degeneration  of,  299 

focal  necrosis  of,  315 

function  of,  74 

hiemochromatosis,  and,  380 

histogenesis  of,  67 

historical  data  concerning, 
51,  59 

hyaline  degeneration  of, 
300,  304,  327 

hypertrophy  of,  341 

inanition,  and,  72 

lesions  affecting  only,  327 

lymphoid  cells  in,  222 

number  of,  62 

pilocarpin,  and,  70 

sclerosis  limited  to,  327 

secretin,  and,  71 

size  of,  61 

transplanted  pancreas  con- 
taining, 345 


Lab-ferment,  84 

Lesser  peritoneal  cavity,  fluid  in,  163 

Levulose,  115 

Lipomatosis,  223 

Lithiasis  (see  Calcidi) 

Lobes  of  pancreas,  19 

Lobules  of  pancreas,  17,  51 

Lymphosarcoma,  291 

M 

Medical  anatomy  of  pancreas,  22 
Myxoedema,  357 

N 

Necrosis,  focal  pancreatic,  314 

hemorrhagic    (see    Hemorrhagic 

necrosis  of  pancreas) 
traumatic,  156 
Nuclear  test  of  Schmidt,  91 
Nuclease,  84 

P 

Pancreas,   experimental   extirpation 
of,  88,  95,  107 

extirpation  of  human,  109 

operation  on,  24 

weight  of,  334 
Pancreas  divisum,  29 
Pancreatic  ajjoplexy,  122 
Pancreatic  juice,  composition  of,  78 
digestion  in  absence  of,  87 
Pancreatin,  184 


INDEX 


387 


Pentosuria,  99 

Peripancreatitis,  161 

Peritonitis  of  lesser  peritoneal  cavity, 

120,  161,  205 
Phloretin,  106 
Phlorhizin  glycosuria,  105 
Pigmentation  of  intestine,  366 
Pilocarpin,  70,  188,  264 
Points  folliculaires,  59 
Prosecretin,  81 
Protein,   absorption  of   {see  Azotor- 

rhcBo) 
Pseudocysts,  266,  269,  283 
Pseudofollicles,  60 

R 
Ranula  pancreatica,  266 

S 

Sahli's  gelatin  capsules,  91 
Sarcoma  of  pancreas,  288,  290 
Schmidt's  nuclear  test,  91 
Secondary  cell-groups,  60 
Secretin,  action  of,  81 

islands  of  Langerhans,  and,  71 
Secretion  of  pancreas,  77,  79 
acid,  and,  79,  80 
acini,  and,  57 
food,  and,  78 
nerves,  and,  80,  81 
Self-digestion  of  pancreas,  85,  123 
Sequestration  of  pancreas,  120,  162, 

170,  178 
Steapsin,  84 
Steatorrhoea,  92 

calculi,  with,  263 
carcinoma,  with,  293 
cyst,  with,  282 
experimental  pancreatic,  87 


S  teatorrhcea . — Continued . 

hemorrhagic  necrosis,  with,  169 
suppurative  pancreatitis,  with, 
206 
Stomach,  relation  to  pancreas,  23 
Struma  of  islands  of  Langerhans,  342 
Succus  entericus,  enterokinase  of,  83 
Suppurative  pancreatitis,  120,  200 

cholelithiasis,  and,  202,  207 

symptoms  of,  205 

treatment  of,  207 
Surgical  anatomy  of  pancreas,  24 
Syphilis,  238,  250 
Syphilitic  pancreatitis,  acquired,  254 

congenital,  250 


Thyroid,   influence   on  pancreas  of, 

115,  356 
Traumatic  necrosis  of  pancreas,  156 
Trypsin,  82 
Trypsinogen,  83 
Tuberculosis,  237,  249 
Tumor,  carcinoma  with,  292,  295 

cyst,  with,_273,  283  _ 

hemorrhagic    necrosis    of    pan- 
creas, with,  169,  173 

U 

Urine  with  pancreatic  disease,   98, 
198 

V 

Vomiting    and    chronic    interstitial 
pancreatitis,  230 


Zymogen,  59,  85 


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